Azaindazoles

ABSTRACT

Herein are disclosed azaindazoles of formula (I) 
                         
where the various groups are defined herein, and which are useful for treating cancer.

This application is a 371 of International Application No.PCT/US2011/035344, filed 5 May 2011, which claims the benefit of U.S.Provisional Application No. 61/332,314, filed 7 May 2010, which areincorporated herein in their entireties.

FIELD OF THE INVENTION

This invention relates to substituted azaindazoles which inhibit EZH2and thus are useful for inhibiting the proliferation of and/or inducingapoptosis in cancer cells.

BACKGROUND OF THE INVENTION

Epigenetic modifications play an important role in the regulation ofmany cellular processes including cell proliferation, differentiation,and cell survival. Global epigenetic modifications are common in cancer,and include global changes in DNA and/or histone methylation,dysregulation of non-coding RNAs and nucleosome remodeling leading toaberrant activation or inactivation of oncogenes, tumor suppressors andsignaling pathways. However, unlike genetic mutations which arise incancer, these epigenetic changes can be reversed through selectiveinhibition of the enzymes involved. Several methylases involved inhistone or DNA methylation are known to be dysregulated in cancer. Thus,selective inhibitors of particular methylases will be useful in thetreatment of proliferative diseases such as cancer.

EZH2 (enhancer of zeste homolog 2; human EZH2 gene: Cardoso, C, et al;European J of Human Genetics, Vol. 8, No. 3 Pages 174-180, 2000) is thecatalytic subunit of the Polycomb Repressor Complex 2 (PRC2) whichfunctions to silence target genes by tri-methylating lysine 27 ofhistone H3 (H3K27me3). Histone H3 is one of the five main histoneproteins involved in the structure of chromatin in eukaryotic cells.Featuring a main globular domain and a long N-terminal tail, Histonesare involved with the structure of the nucleosomes, a ‘beads on astring’ structure. Histone proteins are highly post-translationallymodified however Histone H3 is the most extensively modified of the fivehistones. The term “Histone H3” alone is purposely ambiguous in that itdoes not distinguish between sequence variants or modification state.Histone H3 is an important protein in the emerging field of epigenetics,where its sequence variants and variable modification states are thoughtto play a role in the dynamic and long term regulation of genes.

Increased EZH2 expression has been observed in numerous solid tumorsincluding those of the prostate, breast, skin, bladder, liver, pancreas,head and neck and correlates with cancer aggressiveness, metastasis andpoor outcome (Varambally et al., 2002; Kleer et al., 2003; Breuer etal., 2004; Bachmann et al., 2005; Weikert et al., 2005; Sudo et al.,2005; Bachmann et al., 2006). For instance, there is a greater risk ofrecurrence after prostatectomy in tumors expressing high levels of EZH2,increased metastasis, shorter disease-free survival and increased deathin breast cancer patients with high EZH2 levels (Varambally et al.,2002; Kleer et al., 2003). More recently, inactivating mutations in UTX(ubiquitously transcribed tetratricopeptixe repeats X), a H3K27demethylase which functions in opposition to EZH2, have been identifiedin multiple solid and hematological tumor types (including renal,glioblastoma, esophageal, breast, colon, non-small cell lung, small celllung, bladder, multiple myeloma, and chronic myeloid leukemia tumors),and low UTX levels correlate with poor survival in breast cancersuggesting that loss of UTX function leads to increased H3K27me3 andrepression of target genes (Wang et al., 2010). Together, these datasuggest that increased H3K27me3 levels contribute to canceraggressiveness in many tumor types and that inhibition of EZH2 activitymay provide therapeutic benefit.

Numerous studies have reported that direct knockdown of EZH2 via siRNAor shRNA or indirect loss of EZH2 via treatment with the SAH hydrolaseinhibitor 3-deazaneplanocin A (DZNep) decreases cancer cell lineproliferation and invasion in vitro and tumor growth in vivo (Gonzalezet al., 2008, GBM 2009). While the precise mechanism by which aberrantEZH2 activity leads to cancer progression is not known, many EZH2 targetgenes are tumor suppressors suggesting that loss of tumor suppressorfunction is a key mechanism (refs). In addition, EZH2 overexpression inimmortalized or primary epithelial cells promotes anchorage independentgrowth and invasion and requires EZH2 catalytic activity. (Kleer et al.,2003; Cao et al., 2008).

Thus, there is strong evidence to suggest that inhibition of EZH2activity decreases cellular proliferation and invasion. Accordingly,compounds that inhibit EZH2 activity would be useful for the treatmentof cancer. The azaindazoles of this invention provide such treatment.

SUMMARY OF THE INVENTION

In a first instance, this invention relates to compounds of formula (I)

wherein

X and Z are selected independently from the group consisting ofhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl,(C₆-C₁₀)bicycloalkyl, unsubstituted or substituted heterocycloalkyl,unsubstituted or substituted heterocycloalkyl-(C₁-C₈)alkyl or-(C₂-C₈)alkenyl, unsubstituted or substituted aryl, unsubstituted orsubstituted aryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, halo, cyano, —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SR^(a), —SOR^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b);

Y is H or halo;

R¹ is (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₆-C₁₀)bicycloalkyl, unsubstituted or substitutedheterocycloalkyl or -(C₂-C₈)alkenyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b);

R³ is hydrogen, (C₁-C₈)alkyl, cyano, trifluoromethyl, —NR^(a)R^(b), orhalo;

R⁶ is selected from the group consisting of hydrogen, halo,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—CONR^(a)NR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b),nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),—NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), —OC(O)NR^(a)R^(b);

-   -   wherein any (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,        cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl,        or heteroaryl group is optionally substituted by 1, 2 or 3        groups independently selected from the group consisting of halo,        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NRaSO₂NR^(a)R^(b), —OR^(a),        —OC(O)R^(a), —OC(O)NR^(a)R^(b), heterocycloalkyl, aryl,        heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;        -   wherein any aryl or heteroaryl moiety of said aryl,            heteroaryl, aryl(C₁-C₄)alkyl, or heteroaryl(C₁-C₄)alkyl is            optionally substituted by 1, 2 or 3 groups independently            selected from the group consisting of halo, (C₁-C₆)alkyl,            (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,            cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a),            —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),            —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),            —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a),            —OC(O)R^(a), and —OC(O)NR^(a)R^(b);

R^(a) and R^(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein said(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl,bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionallysubstituted by 1, 2 or 3 groups independently selected from halo,hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, or —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring;

or a salt thereof.

In a further iteration of this invention it relates to a method oftreating cancer.

Another aspect of the invention are pharmaceutical preparationscomprising compounds of formula (I) and pharmaceutically acceptableexcipients.

In a fourth aspect, there is provided the use of a compound of formula(I) or a pharmaceutically acceptable salt or solvate thereof, in thepreparation of a medicament for use in the treatment of a disordermediated by inhibiting EZH2, such as inducing apoptosis in cancer cells.

In a fifth aspect there is provided methods of co-administering thepresently invented compounds of formula (I) with another activeingredients.

DETAILED DESCRIPTION OF THE INVENTION

For the avoidance of doubt, unless otherwise indicated, the term“substituted” means substituted by one or more defined groups. In thecase where groups may be selected from a number of alternative groupsthe selected groups may be the same or different.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different.

An “effective amount” means that amount of a drug or pharmaceuticalagent that will elicit the biological or medical response of a tissue,system, animal or human that is being sought, for instance, by aresearcher or clinician. Furthermore, the term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function.

As used herein the term “alkyl” refers to a straight- or branched-chainhydrocarbon radical having the specified number of carbon atoms, so forexample, as used herein, the terms “C₁-C₈alkyl” refers to an alkyl grouphaving at least 1 and up to 8 carbon atoms respectively. Examples ofsuch branched or straight-chained alkyl groups useful in the presentinvention include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl,n-heptyl, and n-octyl and branched analogs of the latter 5 normalalkanes.

The term “alkoxy” as used herein means —O(C₁-C₈alkyl) including —OCH₃,—OCH₂CH₃ and —OC(CH₃)₃ and the like per the definition of alkyl above.

The term “alkylthio” as used herein is meant —S(C₁-C₈alkyl) including—SCH₃, —SCH₂CH₃ and the like per the definition of alkyl above.

The term “acyloxy” means —OC(O)C₁-C₈alkyl and the like per thedefinition of alkyl above.

“Acylamino” means-N(H)C(O)C₁-C₈alkyl and the like per the definition ofalkyl above.

“Aryloxy” means —O(aryl), —O(substituted aryl), —O(heteroaryl) or—O(substituted heteroaryl).

“Arylamino” means —NH(aryl), —NH(substituted aryl), —NH(heteroaryl) or—NH(substituted heteroaryl), and the like.

When the term “alkenyl” (or “alkenylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon double bonds. Examplesinclude ethenyl (or ethenylene) and propenyl (or propenylene).

When the term “alkynyl” (or “alkynylene”) is used it refers to straightor branched hydrocarbon chains containing the specified number of carbonatoms and at least 1 and up to 5 carbon-carbon triple bonds. Examplesinclude ethynyl (or ethynylene) and propynyl (or propynylene).

“Haloalkyl” refers to an alkyl group group that is substituted with oneor more halo substituents, suitably from 1 to 6 substituents. Haloalkylincludes trifluoromethyl.

When “cycloalkyl” is used it refers to a non-aromatic, saturated, cyclichydrocarbon ring containing the specified number of carbon atoms. So,for example, the term “C₃-C₈cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring having from three to eight carbon atoms. Exemplary“C₃-C₈cycloalkyl” groups useful in the present invention include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The term “C₅-C₈cycloalkenyl” refers to a non-aromatic monocycliccarboxycyclic ring having the specified number of carbon atoms and up to3 carbon-carbon double bonds. “Cycloalkenyl” includes by way of examplecyclopentenyl and cyclohexenyl.

Where “C₃-C₈heterocycloalkyl” is used, it means a non-aromaticheterocyclic ring containing the specified number of ring atoms being,saturated or having one or more degrees of unsaturation and containingone or more heteroatom substitutions independently selected from O, Sand N. Such a ring may be optionally fused to one or more other“heterocyclic” ring(s) or cycloalkyl ring(s). Examples are given hereinbelow.

“Aryl” refers to optionally substituted monocyclic or polycarbocyclicunfused or fused groups having 6 to 14 carbon atoms and having at leastone aromatic ring that complies with Hückel's Rule. Examples of arylgroups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, andthe like, as further illustrated below.

“Heteroaryl” means an optionally substituted aromatic monocyclic ring orpolycarbocyclic fused ring system wherein at least one ring complieswith Hückel's Rule, has the specified number of ring atoms, and thatring contains at least one heteratom independently selected from N, Oand S. Examples of “heteroaryl” groups are given herein below.

The term “optionally” means that the subsequently described event(s) mayor may not occur, and includes both event(s), which occur, and eventsthat do not occur.

Herein, the term “pharmaceutically-acceptable salts” refers to saltsthat retain the desired biological activity of the subject compound andexhibit minimal undesired toxicological effects. Thesepharmaceutically-acceptable salts may be prepared in situ during thefinal isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively.

While the compounds encompassed by the general structure of formula (I)as defined herein are believed to be useful for inducing apoptosis incancer cells, some of these compounds are more active that others. Inthat vein, the following subgroups delineate certain compounds believedto have greater potency or other properties which suggest they may be abetter choice for use in therapy, versus other. Those subgroups arerepresented as follows:

Subgroup A

X and Z are selected from the group consisting of (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR^(a)R^(b), and—OR^(a);

Y is H or F;

R¹ is selected from the group consisting of (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

R³ is selected from the group consisting of hydrogen, (C₁-C₈)alkyl,cyano, trifluoromethyl, —NR^(a)R^(b), and halo;

R⁶ is selected from the group consisting of hydrogen, halo, cyano,trifluoromethyl, amino, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl,heteroaryl, acylamino; (C₂-C₈)alkynyl, arylalkynyl, heteroarylalkynyl;—SO₂R^(a); —SO₂NR^(a)R^(b) and —NR^(a)SO₂R^(b);

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)alkynyl,        arylalkynyl, heteroarylalkynyl group is optionally substituted        by 1, 2 or 3 groups independently selected from halo,        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),        —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), heterocycloalkyl, aryl,        heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

R^(a) and R^(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein said(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl,bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionallysubstituted by 1, 2 or 3 groups independently selected from halo,hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring. An aryl or heteroaryl group in this particular subgroupA is selected independently from the group consisting of furan,thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, oxadiazole,thiadiazole, triazole, tetrazole, benzofuran, benzothiophene,benzoxazole, benzothiazole, phenyl, pyridine, pyridazine, pyrimidine,pyrazine, triazine, tetrazine, quinoline, cinnoline, quinazoline,quinoxaline, and naphthyridine or another aryl or heteroaryl group asfollows:

wherein in (1),

A is O, NH, or S; B is CH or N, and C is hydrogen or C₁-C₈ alkyl; or

wherein in (2),

D is N or C optionally substituted by hydrogen or C₁-C₈ alkyl; or

wherein in (3),

E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4),

J is O, S or CO; or

wherein in (5),

Q is CH or N;

M is CH or N; and

L/(5) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a),—SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —OR^(a),

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, group is optionally        substituted by 1, 2 or 3 groups independently selected from        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),        —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b); wherein R^(a) and R^(b)        are defined as above; or

wherein in 6,

L/(6) is NH or CH₂; or

wherein in 7,

-   -   M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, heterocycloalkyl, —COR^(a), —CO₂R^(a),        —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a),        —SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),        —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b),        —NR^(a)NR^(a)C(O)R^(b), —NR^(a)NR^(a)C(O)NR^(a)R^(b), —OR^(a),    -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl        group is optionally substituted by 1, 2 or 3 groups        independently selected from (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —COR^(a),        —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a),        —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),        —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NRaSO₂R^(b),        —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b);        wherein R^(a) and R^(b) are defined as above; or

wherein in (8),

P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2; or

wherein in (9),

S/(9) and T(9) is C, or S/(9) is C and T(9) is N, or S/(9) is N andT/(9) is C;

R is hydrogen, amino, methyl, trifluoromethyl, halo;

U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SO₂R^(a),—SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),4-(1H-pyrazol-4-yl),

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, group is optionally        substituted by 1, 2 or 3 groups independently selected from        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SOr^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),        —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),        —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OC(O)R^(a),        —OC(O)NR^(a)R^(b); wherein R^(a) and R^(b) are defined as above.

Subgroup B

X and Z are selected independently from the group consisting of(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, heteroaryl,—NR^(a)R^(b), and —OR^(a);

Y is H;

R¹ is (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, or heterocycloalkyl;

R³ is hydrogen, (C₁-C₈)alkyl or halo;

R⁶ is hydrogen, halo, cyano, trifluoromethyl, amino, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, aryl, heteroaryl, acylamino; (C₂-C₈)alkynyl,arylalkynyl, heteroarylalkynyl; —SO₂R^(a): —SO₂NR^(a)R^(b), or—NR^(a)SO₂R^(b);

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)alkynyl,        arylalkynyl, heteroarylalkynyl group is optionally substituted        by 1, 2 or 3 groups independently selected from halo,        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),        —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b), heterocycloalkyl, aryl,        heteroaryl, aryl(C₁-C₄)alkyl, and heteroaryl(C₁-C₄)alkyl;

R^(a) and R^(b) are each independently hydrogen, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein said(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl,bicycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionallysubstituted by 1, 2 or 3 groups independently selected from halo,hydroxyl, (C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl);

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2 or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;

or R^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 6- to 10-membered bridged bicyclic ring systemoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring. Aryl and heteroaryl in this definition are selectedfrom the group consisting of furan, thiophene, pyrrole, oxazole,thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole,tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine,quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine as ora compound of or another aryl or heteroaryl group as follows:

wherein in (1),

A is O, NH, or S; B is CH or N, and C is hydrogen or C₁-C₈ alkyl; or

wherein in (2),

D is N or C optionally substituted by hydrogen or C₁-C₈ alkyl; or

wherein in (3),

E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4),

J is O, S or CO; or

wherein in (5),

Q is CH or N;

M is CH or N; and

L/(5) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂NR^(a),—SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —OR^(a),

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, group is optionally        substituted by 1, 2 or 3 groups independently selected from        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),        —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b),        wherein R^(a) and R^(b) are defined as above; or

wherein in 6,

L/(6) is NH or CH₂; or

wherein in 7,

-   -   M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl,        (C₃-C₈)cycloalkyl, heterocycloalkyl, —COR^(a), —CO₂R^(a),        —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a),        —SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),        —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b),        —NR^(a)NR^(a)C(O)R^(b), —NR^(a)NR^(a)C(O)NR^(a)R^(b), —OR^(a),    -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl        group is optionally substituted by 1, 2 or 3 groups        independently selected from (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,        (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —COR^(a),        —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a),        —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),        —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),        —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b);        wherein R^(a) and R^(b) are defined as above; or

wherein in (8),

P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2; or

wherein in (9),

S/(9) and T(9) is C, or S/(9) is C and T(9) is N, or S/(9) is N andT/(9) is C;

R is hydrogen, amino, methyl, trifluoromethyl, halo;

U is hydrogen, halo, amino, cyano, nitro, trifluoromethyl, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SO₂R^(a),—SO₂NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—OR^(a), 4-(1H-pyrazol-4-yl),

-   -   wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, group is optionally        substituted by 1, 2 or 3 groups independently selected from        (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,        (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),        —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,        —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),        —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),        —OR^(a), —OC(O)Ra, —OC(O)NR^(a)R^(b), wherein R^(a) and R^(b)        are defined as above.

Subgroup C

X is methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, trifluoromethyl, tetrahydropyran,hydroxymethyl, methoxymethyl, or benzyl;

Y is H;

Z is methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or benzyl;

R¹ is isopropyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl,(1-methylethyl)cyclopropyl, 1,1-dioxo-tetrahydrothiophene-3-yl,1-Me-piperidin-4-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl,N,N-dimethyl-1-propanaminyl, benzyl, or 4-pyridyl;

R³ is H, methyl, or Br; and

R⁶ is methyl, bis(1,1-dimethylethyl), bis(1-methylethyl), cyclopropyl,propyl, dimethylamino, ethylamino, (2-hydroxyethyl)amino,2-propen-1-ylamino, 1-piperazinyl, 1-piperidinyl, 4-morpholinyl,4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenylamino,(phenylmethyl)amino, (4-pyridinylmethyl)amino,[2-(2-pyridinylamino)ethyl]amino, 2-(dimethylamino)ethyl]amino,4-pyridinylamino, 4-(aminocarbonyl)phenyl]amino,3-hydroxy-3-methyl-1-butyn-1-yl, 4-pyridinylethynyl, phenylethynyl,2-furanyl, 3-thienyl; 1H-pyrazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl,3-methyl-1H-indazol-5-yl, 1H-1,2,3-benzotriazol-5-yl,2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,2-oxo-2,3-dihydro-1H-indol-6-yl, 2,1,3-benzoxadiazol-5-yl,2-amino-6-quinazolinyl, 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl,2-amino-5-pyrimidinyl, 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl,phenyl, 2-methylphenyl, 2-nitrophenyl, 2-phenylethyl, 3-aminophenyl,4-aminophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(methyloxy)phenyl,3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 4-(aminocarbonyl)phenyl,4-(1H-pyrazol-4-yl)phenyl, 4-(aminosulfonyl)phenyl,4-(methylsulfonyl)phenyl, 4-[(dimethylamino)sulfonyl]phenyl,4-[(methylamino)carbonyl]phenyl, 4-[(methylamino)sulfonyl]phenyl,4-[(methylsulfonyl)amino]phenyl, 3-pyridinyl, 4-pyridinyl,2-(4-morpholinyl)-4-pyridinyl, 2-amino-4-pyridinyl,5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl,5-[(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl,5-[(phenylsulfonyl)amino]-3-pyridinyl,6-(4-methyl-1-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl,6-(acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl,6-(methyloxy)-3-pyridinyl, 6-[(methylamino)carbonyl]-3-pyridinyl,6-[(methylamino)sulfonyl]-3-pyridinyl, 6-methyl-3-pyridinyl,4-pyridinyloxy.

Individual compounds can be found in the Examples set out below.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of one or more additional pharmaceuticallyactive compounds, whether for treating cancer, the side effects ofcancer or cancer therapy, or some other disease. Preferably, if theadministration is not simultaneous, the compounds are administered in aclose time proximity to each other. Furthermore, it does not matter ifthe compounds are administered in the same dosage form, e.g. onecompound may be administered topically and another compound may beadministered orally.

In certain embodiments, compounds according to Formula I may contain anacidic functional group, one acidic enough to form salts. Representativesalts include pharmaceutically-acceptable metal salts such as sodium,potassium, lithium, calcium, magnesium, aluminum, and zinc salts;carbonates and bicarbonates of a pharmaceutically-acceptable metalcation such as sodium, potassium, lithium, calcium, magnesium, aluminum,and zinc; pharmaceutically-acceptable organic primary, secondary, andtertiary amines including aliphatic amines, aromatic amines, aliphaticdiamines, and hydroxy alkylamines such as methylamine, ethylamine,2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine,ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain abasic functional group and are therefore capable of formingpharmaceutically-acceptable acid addition salts by treatment with asuitable acid. Suitable acids include pharmaceutically-acceptableinorganic acids and pharmaceutically-acceptable organic acids.Representative pharmaceutically-acceptable acid addition salts includehydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate,formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate,malonate, laurate, glutarate, glutamate, estolate, methanesulfonate(mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate,benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate(tosylate) and napthalene-2-sulfonate.

All tautomeric forms of the compounds described herein, includingmixtures thereof, are intended to be encompassed within the scope of theinvention. Generally, the compounds exemplified herein have beenassigned names based on the structure of the tautomer of formula (IA).It should be understood that any reference to named compounds of thisinvention is intended to encompass all tautomers of the named compoundsand any mixtures of tautomers of the named compounds.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be solvated,e.g. as the hydrate. This invention includes within its scopestoichiometric solvates (e.g. hydrates) as well as compounds containingvariable amounts of solvent (e.g. water).

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers. Thecompounds claimed below include mixtures of enantiomers as well aspurified enantiomers or enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by formula (I), or claimed below, as well asany wholly or partially equilibrated mixtures thereof. The presentinvention also covers the individual isomers of the claimed compounds asmixtures with isomers thereof in which one or more chiral centers areinverted.

Where there are different isomeric forms they may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

While it is possible that, for use in therapy, a compound of formula(I), as well as salts, solvates and the like, may be administered as aneat preparation, i.e. no additional carrier, the more usual practice isto present the active ingredient confected with a carrier or diluent.Accordingly, the invention further provides pharmaceutical compositions,which includes a compound of formula (I) and salts, solvates and thelike, and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The compounds of formula (I) and salts, solvates, etc, areas described above. The carrier(s), diluent(s) or excipient(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Inaccordance with another aspect of the invention there is also provided aprocess for the preparation of a pharmaceutical formulation includingadmixing a compound of the formula (I), or salts, solvates etc, with oneor more pharmaceutically acceptable carriers, diluents or excipients.

It will be appreciated by those skilled in the art that certainprotected derivatives of compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. Further, certain compounds ofthe invention may act as prodrugs of other compounds of the invention.All protected derivatives and prodrugs of compounds of the invention areincluded within the scope of the invention. It will further beappreciated by those skilled in the art, that certain moieties, known tothose skilled in the art as “pro-moieties” may be placed on appropriatefunctionalities when such functionalities are present within compoundsof the invention. Preferred prodrugs for compounds of the inventioninclude: esters, carbonate esters, hemi-esters, phosphate esters, nitroesters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds,phosphamides, glycosides, ethers, acetals and ketals.

Treatments

The compounds and compositions of the invention are used to treatcellular proliferation diseases. Disease states which can be treated bythe methods and compositions provided herein include, but are notlimited to, cancer (further discussed below), autoimmune disease, fungaldisorders, arthritis, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. It is appreciated thatin some cases the cells may not be in a hyper or hypo proliferationstate (abnormal state) and still requires treatment. For example, duringwound healing, the cells may be proliferating “normally”, butproliferation enhancement may be desired. Thus, in one embodiment, theinvention herein includes application to cells or individuals afflictedor impending affliction with any one of these disorders or states.

The compositions and methods provided herein are particularly deemeduseful for the treatment of cancer including tumors such as prostate,breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.They are particularly useful in treating metastatic or malignant tumors.More particularly, cancers that may be treated by the compositions andmethods of the invention include, but are not limited to tumor typessuch as astrocytic, breast, cervical, colorectal, endometrial,esophageal, gastric, head and neck, hepatocellular, laryngeal, lung,oral, ovarian, prostate and thyroid carcinomas and sarcomas. Morespecifically, these compounds can be used to treat: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia (acute and chronic), acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one or related of theabove identified conditions.

The instant compounds can be combined with or co-administered with othertherapeutic agents, particularly agents that may enhance the activity ortime of disposition of the compounds. Combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and the use of at least one other treatment method. In oneembodiment, combination therapies according to the invention comprisethe administration of at least one compound of the invention andsurgical therapy. In one embodiment, combination therapies according tothe invention comprise the administration of at least one compound ofthe invention and radiotherapy. In one embodiment, combination therapiesaccording to the invention comprise the administration of at least onecompound of the invention and at least one supportive care agent (e.g.,at least one anti-emetic agent). In one embodiment, combinationtherapies according to the present invention comprise the administrationof at least one compound of the invention and at least one otherchemotherapeutic agent. In one particular embodiment, the inventioncomprises the administration of at least one compound of the inventionand at least one anti-neoplastic agent. In yet another embodiment, theinvention comprises a therapeutic regimen where the EZH2 inhibitors ofthis disclosure are not in and of themselves active or significantlyactive, but when combined with another therapy, which may or may not beactive as a standalone therapy, the combination provides a usefultherapeutic outcome.

By the term “co-administering” and derivatives thereof as used herein ismeant either simultaneous administration or any manner of separatesequential administration of an EZH2 inhibiting compound, as describedherein, and a further active ingredient or ingredients, known to beuseful in the treatment of cancer, including chemotherapy and radiationtreatment. The term further active ingredient or ingredients, as usedherein, includes any compound or therapeutic agent known to or thatdemonstrates advantageous properties when administered to a patient inneed of treatment for cancer. Preferably, if the administration is notsimultaneous, the compounds are administered in a close time proximityto each other. Furthermore, it does not matter if the compounds areadministered in the same dosage form, e.g. one compound may beadministered topically and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus asusceptible tumor being treated may be co-administered in the treatmentof specified cancers in the present invention. Examples of such agentscan be found in Cancer Principles and Practice of Oncology by V. T.Devita and S. Hellman (editors), 6^(th) edition (Feb. 15, 2001),Lippincott Williams & Wilkins Publishers. A person of ordinary skill inthe art would be able to discern which combinations of agents would beuseful based on the particular characteristics of the drugs and thecancer involved. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to, anti-microtubule agents suchas diterpenoids and vinca alkaloids; platinum coordination complexes;alkylating agents such as nitrogen mustards, oxazaphosphorines,alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such asanthracyclins, actinomycins and bleomycins; topoisomerase II inhibitorssuch as epipodophyllotoxins; antimetabolites such as purine andpyrimidine analogues and anti-folate compounds; topoisomerase Iinhibitors such as camptothecins; hormones and hormonal analogues; DNAmethyltransferase inhibitors such as azacitidine and decitabine; signaltransduction pathway inhibitors; non-receptor tyrosine kinaseangiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents;and cell cycle signaling inhibitors.

Typically, any chemotherapeutic agent that has activity against asusceptible neoplasm being treated may be utilized in combination withthe compounds the invention, provided that the particular agent isclinically compatible with therapy employing a compound of theinvention. Typical anti-neoplastic agents useful in the presentinvention include, but are not limited to: alkylating agents,anti-metabolites, antitumor antibiotics, antimitotic agents, nucleosideanalogues, topoisomerase I and II inhibitors, hormones and hormonalanalogues; retinoids, histone deacetylase inhibitors; signaltransduction pathway inhibitors including inhibitors of cell growth orgrowth factor function, angiogenesis inhibitors, and serine/threonine orother kinase inhibitors; cyclin dependent kinase inhibitors; antisensetherapies and immunotherapeutic agents, including monoclonals, vaccinesor other biological agents.

Nucleoside analogues are those compounds which are converted todeoxynucleotide triphosphates and incorporated into replicating DNA inplace of cytosine. DNA methyltransferases become covalently bound to themodified bases resulting in an inactive enzyme and reduced DNAmethylation. Examples of nucleoside analogues include azacitidine anddecitabine which are used for the treatment of myelodysplastic disorder.Histone deacetylase (HDAC) inhibitors include vorinostat, for thetreatment of cutaneous T-cell lymphoma. HDACs modify chromatin throughthe deactylation of histones. In addition, they have a variety ofsubstrates including numerous transcription factors and signalingmolecules. Other HDAC inhibitors are in development.

Signal transduction pathway inhibitors are those inhibitors which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation orsurvival. Signal transduction pathway inhibitors useful in the presentinvention include, but are not limited to, inhibitors of receptortyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domainblockers, serine/threonine kinases, phosphatidyl inositol-3-OH kinases,myoinositol signaling, and Ras oncogenes. Signal transduction pathwayinhibitors may be employed in combination with the compounds of theinvention in the compositions and methods described above.

Receptor kinase angiogenesis inhibitors may also find use in the presentinvention. Inhibitors of angiogenesis related to VEGFR and TIE-2 arediscussed above in regard to signal transduction inhibitors (both arereceptor tyrosine kinases). Other inhibitors may be used in combinationwith the compounds of the invention. For example, anti-VEGF antibodies,which do not recognize VEGFR (the receptor tyrosine kinase), but bind tothe ligand; small molecule inhibitors of integrin (alpha_(v) beta₃) thatinhibit angiogenesis; endostatin and angiostatin (non-RTK) may alsoprove useful in combination with the compounds of the invention. Oneexample of a VEGFR antibody is bevacizumab (AVASTIN®).

Several inhibitors of growth factor receptors are under development andinclude ligand antagonists, antibodies, tyrosine kinase inhibitors,anti-sense oligonucleotides and aptamers. Any of these growth factorreceptor inhibitors may be employed in combination with the compounds ofthe invention in any of the compositions and methods/uses describedherein. Trastuzumab (Herceptin®) is an example of an anti-erbB2 antibodyinhibitor of growth factor function. One example of an anti-erbB1antibody inhibitor of growth factor function is cetuximab (Erbitux™,C225). Bevacizumab (Avastin®) is an example of a monoclonal antibodydirected against VEGFR. Examples of small molecule inhibitors ofepidermal growth factor receptors include but are not limited tolapatinib (Tykerb™) and erlotinib (TARCEVA®). Imatinib mesylate(GLEEVEC®) is one example of a PDGFR inhibitor. Examples of VEGFRinhibitors include pazopanib, ZD6474, AZD2171, PTK787, sunitinib andsorafenib.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. It was first isolated in 1971 by Wani et al. J. Am.Chem, Soc., 93:2325. 1971), who characterized its structure by chemicaland X-ray crystallographic methods. One mechanism for its activityrelates to paclitaxel's capacity to bind tubulin, thereby inhibitingcancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA,77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar,J. Biol, Chem, 256: 10435-10441 (1981). For a review of synthesis andanticancer activity of some paclitaxel derivatives see: D. G. I.Kingston et al., Studies in Organic Chemistry vol. 26, entitled “Newtrends in Natural Products Chemistry 1986”, Attaur-Rahman, P. W. LeQuesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

Paclitaxel has been approved for clinical use in the treatment ofrefractory ovarian cancer in the United States (Markman et al., YaleJournal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann.intern, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine, N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine,3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate(1:2)(salt)], commercially available as an injectable solution ofvinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid.Vinorelbine is indicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer. The primary dose limiting side effects of cisplatin arenephrotoxicity, which may be controlled by hydration and diuresis, andototoxicity.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′],is commercially available as PARAPLATIN® as an injectable solution.Carboplatin is primarily indicated in the first and second linetreatment of advanced ovarian carcinoma. Bone marrow suppression is thedose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea,vomiting and leukopenia are the most common dose limiting side effectsof cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-resectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease. Bone marrow suppression is the most common doselimiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia. Bone marrow suppression is the mostcommon dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppressionis the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are themost common dose limiting side effects of dacarbazine.

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also know as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, andanorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Myelosuppression is the most common dose limiting side effectof daunorubicin.

Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Myelosuppression is the most common dose limiting side effectof doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneoustoxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Myelosuppression is the most common sideeffect of etoposide. The incidence of leucopenia tends to be more severethan thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.Myelosuppression is the most common dose limiting side effect ofteniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Myelosuppression and mucositis are dose limitingside effects of 5-fluorouracil. Other fluoropyrimidine analogs include5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridinemonophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabineinduces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. Myelosuppression and gastrointestinal mucositis are expectedside effects of mercaptopurine at high doses. A useful mercaptopurineanalog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of thioguanine administration.However, gastrointestinal side effects occur and can be dose limiting.Other purine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.Myelosuppression, including leucopenia, thrombocytopenia, and anemia, isthe most common dose limiting side effect of gemcitabine administration.

Methotrexate,N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.Myelosuppression (leucopenia, thrombocytopenia, and anemia) andmucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl,(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with itsactive metabolite SN-38, to the topoisomerase I-DNA complex. It isbelieved that cytotoxicity occurs as a result of irreparable doublestrand breaks caused by interaction of the topoisomerase I: DNA:irintecan or SN-38 ternary complex with replication enzymes. Irinotecanis indicated for treatment of metastatic cancer of the colon or rectum.The dose limiting side effects of irinotecan HCl are myelosuppression,including neutropenia, and GI effects, including diarrhea.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I-DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer. The doselimiting side effect of topotecan HCl is myelosuppression, primarilyneutropenia.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalcompositions may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage compositions are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient. Furthermore, such pharmaceutical compositions may beprepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such compositions maybe prepared by any method known in the art of pharmacy, for example bybringing into association a compound of formal (I) with the carrier(s)or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by tablet forming dies by means ofthe addition of stearic acid, a stearate salt, talc or mineral oil. Thelubricated mixture is then compressed into tablets. The compounds of thepresent invention can also be combined with a free flowing inert carrierand compressed into tablets directly without going through thegranulating or slugging steps. A clear or opaque protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of a compound of formula (I). Syrups can be prepared bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a non-toxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxy ethylene sorbitol ethers, preservatives, flavoradditive such as peppermint oil or natural sweeteners or saccharin orother artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit pharmaceutical compositions for oraladministration can be microencapsulated. The formulation can also beprepared to prolong or sustain the release as for example by coating orembedding particulate material in polymers, wax or the like.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe composition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The pharmaceutical compositions may bepresented in unit-dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample water for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the pharmaceutical compositions may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the intended recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant prescribing the medication. However, an effective amountof a compound of formula (I) for the treatment of anemia will generallybe in the range of 0.001 to 100 mg/kg body weight of recipient per day,suitably in the range of 0.01 to 10 mg/kg body weight per day. For a 70kg adult mammal, the actual amount per day would suitably be from 7 to700 mg and this amount may be given in a single dose per day or in anumber (such as two, three, four, five or six) of sub-doses per day suchthat the total daily dose is the same. An effective amount of a salt orsolvate, etc., may be determined as a proportion of the effective amountof the compound of formula (I) per se. It is envisaged that similardosages would be appropriate for treatment of the other conditionsreferred to above.

Chemical Background

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention as prepared are given in theexamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds offormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

EXAMPLES General Experimental Methods

The following abbreviations are used throughout the experimental andhave the following meaning:

aq aqueous

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binapthyl

ca. circa

CDCl₃-d chloroform-d

CD₃OD-d₄ methanol-d₄

Cs₂CO₃ cesium carbonate

CHCl₃ chloroform

ACN acetonitrile

CH₃CN acetonitrile

Celite® registered trademark of Celite Corp. brand of diatomaceous earth

DBU 1,8-diazabicyclo[5.4.0]undeca-7-ene

DCE dichloroethane

DCM methylene chloride

DME 1,2 dimethoxyethane

DMF N,N-dimethyl formamide

DIEA diisopropyl ethylamine

DMSO-d₆ dimethylsulfoxide-d₆

EtOAc ethyl acetate

EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodimmide hydrochloride

h hour(s)

¹H NMR proton nuclear magnetic resonance

HCl hydrochloric acid

HOAT 1-hydroxy-7-azabenzotriazole

HPLC high performance liquid chromatography

IPA 2-propanol

K₂CO₃ potassium carbonate

KOH potassium hydroxide

LC/MS liquid chromatography/mass spectroscopy

MgSO₄ magnesium sulfate

MeOH methanol

min minute(s)

MTBE methyl tert-butyl ether

MS mass spectrometry

NaOH sodium hydroxide

Na₂SO₄ sodium sulfate

NH₄OH ammonium hydroxide

NMM 4-methylmorpholine

NMP N-methyl-2-pyrrolidone

Pd/C palladium (10% by wt) on carbon

PdCl₂(dppf)-CH₂Cl₂1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex

Pd(Ph₃P)₄ tetrakis(triphenylphosphine)palladium(0)

SOCl₂ thionyl chloride

SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

TFA trifluoroacetic acd

THF tetrahydrofuran

TLC thin layer chromatography

The following guidelines apply to all experimental procedures describedherein. All reactions were conducted under a positive pressure ofnitrogen using oven-dried glassware, unless otherwise indicated.Temperatures designated are external (i.e. bath temperatures), and areapproximate. Air and moisture-sensitive liquids were transferred viasyringe. Reagents were used as received. Solvents utilized were thoselisted as “anhydrous” by vendors. Molarities listed for reagents insolutions are approximate, and were used without prior titration againsta corresponding standard. All reactions were agitated by stir bar,unless otherwise indicated. Heating was conducted using heating bathscontaining silicon oil, unless otherwise indicated. Reactions conductedby microwave irradiation (0-400 W at 2.45 GHz) were done so using aBiotage Initiator™ 2.0 instrument with Biotage microwave EXP vials(0.2-20 mL) and septa and caps. Irradiation levels utilized (i.e. high,normal, low) based on solvent and ionic charge were based on vendorspecifications. Cooling to temperatures below −70° C. was conductedusing dry ice/acetone or dry ice/2-propanol. Magnesium sulfate andsodium sulfate used as drying agents were of anhydrous grade, and wereused interchangeably. Solvents described as being removed “in vacuo” or“under reduced pressure” were done so by rotary evaporation.

Preparative normal phase silica gel chromatography was carried out usingeither a Teledyne ISCO CombiFlash Companion instrument with RediSep orISCO Gold silica gel cartridges (4 g-330 g), or an Analogix IF280instrument with SF25 silica gel cartridges (4 g-3-00 g), or a BiotageSP1 instrument with HP silica gel cartridges (10 g-100 g). Purificationby reverse phase HPLC was conducted using a YMC-pack column (ODS-A 75×30mm) as solid phase, unless otherwise noted. A mobile phase of 25 mL/minA (acetonitrile-0.1% TFA): B (water-0.1% TFA), 10-80% gradient A (10min) was utilized, with UV detection at 214 nM, unless otherwise noted.

A PE Sciex API 150 single quadrupole mass spectrometer (PE Sciex,Thornhill, Ontario, Canada) was operated using electrospray ionizationin the positive ion detection mode. The nebulizing gas was generatedfrom a zero air generator (Balston Inc., Haverhill, Mass., USA) anddelivered at 65 psi and the curtain gas was high purity nitrogendelivered from a Dewar liquid nitrogen vessel at 50 psi. The voltageapplied to the electrospray needle was 4.8 kV. The orifice was set at 25V and mass spectrometer was scanned at a rate of 0.5 scan/sec using astep mass of 0.2 amu and collecting profile data.

Method A LCMS. Samples were introduced into the mass spectrometer usinga CTC PAL autosampler (LEAP Technologies, Carrboro, N.C.) equipped witha hamilton 10 uL syringe which performed the injection into a Valco10-port injection valve. The HPLC pump was a Shimadzu LC-10ADvp(Shimadzu Scientific Instruments, Columbia, Md.) operated at 0.3 mL/minand a linear gradient 4.5% A to 90% B in 3.2 min. with a 0.4 min. hold.The mobile phase was composed of 100% (H₂O 0.02% TFA) in vessel A and100% (CH₃CN 0.018% TFA) in vessel B. The stationary phase is Aquasil(C18) and the column dimensions were 1 mm×40 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method B, LCMS. Alternatively, an Agilent 1100 analytical HPLC systemwith an LC/MS was used and operated at 1 mL/min and a linear gradient 5%A to 100% B in 2.2 min with a 0.4 min hold. The mobile phase wascomposed of 100% (H₂O 0.02% TFA) in vessel A and 100% (CH₃CN 0.018% TFA)in vessel B. The stationary phase was Zobax (C8) with a 3.5 um particalsize and the column dimensions were 2.1 mm×50 mm. Detection was by UV at214 nm, evaporative light-scattering (ELSD) and MS.

Method C, LCMS. Alternatively, an MDSSCIEX API 2000 equipped with acapillary column of (50×4.6 mm, 5 μm) was used. HPLC was done onAgilent-1200 series UPLC system equipped with column Zorbax SB-C18(50×4.6 mm, 1.8 μm) eluting with CH₃CN: ammonium acetate buffer. Thereactions were performed in the microwave (CEM, Discover).

¹H-NMR spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHzinstrument, with ACD Spect manager v. 10 used for reprocessing.Multiplicities indicated are: s=singlet, d=doublet, t=triplet,q=quartet, quint=quintet, sxt=sextet, m=multiplet, dd=doublet ofdoublets, dt=doublet of triplets etc. and br indicates a broad signal.

Analytical HPLC: Products were analyzed by Agilent 1100 AnalyticalChromatography system, with 4.5×75 mm Zorbax XDB-C18 column (3.5 um) at2 mL/min with a 4 min gradient from 5% CH₃CN (0.1% formic acid) to 95%CH₃CN (0.1% formic acid) in H₂O (0.1% formic acid) and a 1 min hold.

The compounds of the present invention were prepared according to thefollowing schemes 1-4 described in detail below. The groups andsubstituents shown in the schemes 1-4, such as X, Y, Z and the various Rgroups have the same definition in what follows as they have hereinabove. The solvents and conditions referred to are illustrative and arenot intended to be limiting.

Scheme 1 illustrates two methods to synthesize a compound of formula(VII). Substituted aminopyrazoles of formula (I) are heated with diethyloxobutanedione in benzene or toluene at 62° C. overnight. Treatment ofthe putative intermediate with acetic acid and typically heating atreflux furnishes azaindazole compounds of formula (II). Compounds offormula (II) are converted to compounds of formula (III) bybase-catalyzed hydrolysis of the ethyl ester and then chlorination ofthe putative carboxylic acid intermediate with POCl₃ under standardconditions to afford compounds of formula (IV). Treatment of compoundsof formula (IV) with substituted aminomethylpyridones of formula (V)using EDC, HOAT, N-methylmorpholine, and DMSO for a period of no lessthan 12 h stirring typically at room temperature (in some instances,heating at 40° C. may be required), affords compounds of formula (VI).Compounds of formula (VI) are substituted at the 6-position usingstandard methods known to those skilled in the art (i.e. nucleophillicsubstitution, palladium mediated cross couplings), to afford compoundsof formula (VII). Alternatively, compounds of formula (VII) can beobtained from a compound of formula (II) via compounds (IIa) and (IVa).In this route, compounds of formula (II) are converted to thecorresponding triflate (IIa) using standard methods. Compounds offormula (IIa) are then substituted at the 6-pos. using standardpalladium mediated cross-coupling conditions, followed by base-catalyzedhydrolysis of the ethyl ester group to afford compounds of formula(IVa). Treatment of compounds of formula (IVa) with substitutedaminomethylpyridones of formula (V) using EDC, HOAT, N-methylmorpholine,and DMSO at room temperature for a period of no less than 12 h stirringat room temperature affords compounds of formula (VII).

Compounds of formula (VII) are also prepared as depicted in scheme 2. Inthis embodiment, substituted oxobutanediones of formula (VIII) (preparedby Claisen condensation between an appropriately substitutued ketone anddiethyloxalate) are heated with substituted aminopyrazoles of formula(I) (as described for scheme 1), to afford compounds of formula (IX).Compounds of formula (IX) are converted to compounds of formula (X) bybase-catalyzed hydrolysis. Substitutions respectively at either theR3-position, or on the R6 substituted group of compounds of formulas(IX) and (X) are done so using methods known to those skilled in the art(e.g. bromination, nitration). Treatment of compounds of formula (X)with substituted aminomethylpyridones of formula (V) using EDC, HOAT,N-methylmorpholine, and DMSO at room temperature for a period no lessthan 12 h stirring at room temperature, affords compounds of formula(VII).

Compounds of formula (VII) are also prepared as depicted in scheme 3. Inthis embodiment, substituted aminopyrazoles of formula (I) are heatedwith a keto-ester of formula (XI) in benzene containing catalytic aceticacid at 62° C. overnight. Exposure of the putative intermediate torefluxing Dowtherm A overnight affords a compound of formula (XII).Compounds of formula (XI) that are not commercially available areprepared using standard methods known to those skilled in the art, andare described herein. Compounds of formula (XII) are converted tocompounds of formula (XIII) by bromination with refluxing POBr₃ intoluene/DMF for 1 h. Heating of compounds of formula (XIII) with dicyanozinc, tris(dibenzylideneacetone)dipalladium(0), and SPhos in DMFandwater at 120° C. for 2 hours furnishes compounds of formula (XIV). Thecompounds of formula (XIV) are hydrolyzed to the compounds of formula(X) using standard base-catalyzed hydrolysis conditions.

Compounds of formula (X) are treated with substitutedaminomethylpyridones of formula (V) using EDC, HOAT, N-methylmorpholine,and DMSO at room temperature for a period no less than 12 h stirring atroom temperature, to afford compounds of formula (VII).

Scheme 4 illustrates the method to synthesize a compound of formula (V).Heating of compounds of formula (XV) with cyanoacetamide in ethanol atreflux containing catalytic piperidine for typically 30 min, affordscompounds of formula (XVII). Alternatively, treatment of compounds offormula (XVI) with cyanoacetamide in DMSO at room temperature with anexcess of potassium tert-butoxide under an atmosphere of oxygen for ca.90 min. also affords compounds of formula (XVII). Regioisomericmixtures, are separable and the individual compounds regiochemicalassignments can be confirmed by 2D HNMR techniques. Compounds of formula(XV) and (XVI) which are not commercially available are prepared usingstandard methods known to those skilled in the art, and are describedherein. Compounds of formula (XVII) can be converted to compounds offormula (V) either by hydrogenation using sodium acetate, palladium oncarbon, and platinum oxide, or reduction conditions using NaBH₄ witheither iodine or NiCl₂-6H₂O.

Examples Intermediate 16-Hydroxy-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

Step 1 1-(1-methylethyl)-1H-pyrazol-5-amine

To a solution of ethyl (2Z)-2-cyano-3-(ethyloxy)-2-propenoate (114.2 g,0.67 mol) in ethanol (250 mL) was slowly added isopropylhydrazine (55 g,0.74 mol) in a dropwise manner. The mixture was heated at reflux for 4h, and then cooled to room temperature. The mixture was concentrated invacuo. Approximately half of the crude5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid ethyl ester (50 g) wassuspended in an aqueous solution of sodium hydroxide (4M, 130 mL), andstirred with heating at reflux for 2 h. The reaction mixture was thencooled to room temperature and adjusted to pH=3.5 with concentrated HCl,wherein precipitate formation ensued. The solid was collected byfiltration and dried in vacuum oven overnight to afford crude5-amino-1-isopropyl-1H-pyrazole-4-carboxylic acid (30 g). The solid wassuspended in diphenyl ether (120 mL) and stirred with heating at160-165° C. for 2 h. The solution was then cooled to room temperatureand the solvent removed in vacuo. The crude product was purified bysilica gel chromatography (eluent: petroleum ether/EtOAc=1:1) to affordthe product as 12 g. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (d, 6H, J=6.4Hz), 4.32 (m, 1H), 5.06 (s, 2H), 5.21 (s, 1H), 7.00 (s, 1H).

Step 2

To a solution of diethyl 2-oxobutanedione (96 g) in toluene (500 mL) wasadded 1-(1-methylethyl)-1H-pyrazol-5-amine (30 g, 0.24 mol) and themixture was stirred at 60° C. overnight. The mixture was concentrated invacuo, the crude residue dissolved into acetic acid (500 mL), and thenheated at reflux for 2 h. The mixture was then cooled to roomtemperature and concentrated in vacuo to give a residue, which wasrecrystallized from DCM to afford the product as a yellow colored solid,collected as 40 g. This solid was suspended in in ethanol (700 mL) andTHF (100 mL), followed by addition of 3 M NaOH (150 mL). The reactionmixture was stirred at 40° C. for 40 min. The mixture was concentratedin vacuo to remove the volatiles, and the aqueous layer then acidifiedusing 1M HCl. The resulting precipitate was collected by filtration anddried under high vacuum to give the title compound,6-hydroxy-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid, as 27 g. LCMS E-S (M+H)=222.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.48 (d, J=6.82 Hz, 6H), 4.89-4.96 (m, 1H), 6.81 (s, 1H), 8.13 (s, 1H).

Intermediate 23-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

Step 1 3-Methyl-1-(1-methylethyl)-1H-pyrazol-5-amine

3-Amino-2-butenenitrile (33.3 g, 0.41 mol) and ethanol (170 mL) werecombined and stirred at room temperature for 30 min., after which timeisopropylhydrazine (50 g, 0.67 mol) was added at once. After stirring atroom temperature for 5 min., the contents were then heated at reflux for10 h. After cooling to room temperature, the mixture was concentrated invacuo to give the desired product (85 g) which was used in the next stepdirectly. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.21 (d, 6H, J=6.4 Hz), 1.94(s, 3H), 4.21 (m, 1H), 4.93 (s, 2H), 5.02 (s, 1H).

Step 2

To a solution of diethyl 2-oxobutanedione (176 g, 0.94 mol) in toluene(2 L) was added 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (82.5 g,0.59 mol), and the mixture stirred at 62° C., overnight. After coolingto room temperature, the mixture was concentrated in vacuo and the cruderesidue dissolved into acetic acid (1.5 L). The mixture was heated atreflux for 2 h. After cooling to room temperature, the mixture wasconcentrated in vacuo to afford a solid residue, which wasrecrystallized from DCM to afford the desired product as a yellowcolored solid. The collected solid was suspended in ethanol (1510 mL)and THF (216 mL) followed by addition of 3N NaOH (334 mL) and thereaction mixture was stirred at 40° C. for 40 min. The mixture wasconcentrated in vacuo to remove the volatiles and the aqueous phaseacidified using 1N HCl. The resulting precipitate was collected byfiltration and dried under high vacuum to give the title compound,3-methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid, as 51.38 g. LCMS E-S (M+H)=236.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.35 (d, J=6.8 Hz, 6H), 2.41 (s, 3H), 4.84-4.91 (m, 1H), 6.64 (s, 1H).Carboxylic acid proton not observed.

Intermediate 3 Ethyl1-(1,1-dimethylethyl)-6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

1-(1,1-Dimethylethyl)-3-methyl-1H-pyrazol-5-amine (5 g, 32.6 mmol),diethyl 2-oxobutanedione (6.14 g, 32.6 mmol) and toluene (100 mL) wereheated at 70° C. for 16 hours. The solvent was removed in vacuo, thecrude residue dissolved in acetic acid (100 mL), and heated at refluxfor 4 hours. The solvent was removed in vacuo, and the crude productpurified via silica gel chromatography (eluent: gradient of 0 to 10%EtOAc/Hexanes). The product was collected as a solid, 6.32 g (70%). LCMSE-S (M+H)=278.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.39 (s, 1H), 6.82 (s,1H), 4.36 (q, 2H, J=7.2 Hz), 2.45 (s, 3H), 1.69 (s, 9H), 1.32 (t, 3H,J=7.2 Hz).

Intermediate 41-(1,1-Dimethylethyl)-6-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

Sodium hydroxide (52.6 mL, 52.6 mmol) was added to an EtOH solution (100mL) of ethyl1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(7.3 g, 26.3 mmol) and stirred at room temperature for 16 h. The solventwas removed in vacuo. The crude residue was suspended in water, andextracted with EtOAc. The combined organic layers were washed withwater, dried over MgSO₄, filtered, and concentrated in vacuo. The solidproduct obtained was set aside. The aqueous phase was concentrated invacuo and the crude product purified by reverse phase HPLC (mobilephase: 20-50% ACN/H₂O, 0.1% TFA) to afford additional product. Thecombined products were collected as a solid, 5.76 g (88%). LCMS E-S(M+H)=250.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.5-13.9 (br s, 1H),11.2-11.5 (br s, 1H), 6.78 (s, 1H), 2.46 (s, 3H), 1.70 (s, 9H).

Intermediate 56-Chloro-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To a 75 mL pressure vessel was added1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (4.12 g, 18.62 mmol), followed by phosphorous oxychloride (26.0 ml,279 mmol). The flask was sealed and the stirring mixture heated at ca.105° C. for ca. 18 h. After cooling to room temperature, the contentswere concentrated in vacuo to remove most of volatiles. The residualcontents were poured into a mixture of ice and 3M NaOH (60 mL), followedby additional 3M NaOH to ensure the pH stayed basic. The mixture wasstirred for 30 min., and then cooled in an ice bath. The heterogenousmixture was slowly acidified to pH=3-4 with 6M HCl. The resultingsuspension was extracted with EtOAc (3×). The combined organic layerswere dried over MgSO₄, filtered, and concentrated in vacuo to afford ayellow solid which was dried in a hi-vac oven overnight. The titlecompound was collected as 4.11 g (90%), and used without furtherpurification. LCMS E-S (M+H)=240.2/242.2. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.51 (d, J=6.57 Hz, 6H) 5.17 (quin, J=6.63 Hz, 1H) 7.65 (s, 1H) 8.41(s, 1H) 14.25 (br. s., 1H).

Intermediate 66-Chloro-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

3-Methyl-1-(1-methylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (1.5 g, 6.38 mmol) was added to a solution of THF (15 mL) followedby addition of phosphorous oxychloride (8.9 mL, 96 mmol), and thecontents heated at 105° C. overnight. After cooling to room temperature,the contents were concentrated in vacuo to remove most of the volatiles.The residual contents were slowly poured into a solution of iced waterand 1N NaOH (10 mL), and the contents were stirred at room temperaturefor 24 h, during which time solid precipitation ensued. Additional 1NNaOH was added, upon which the solids went into solution. After stirringat room temperature for an additional 30 min., the contents were cooledin an ice bath and the mixture slowly acidified to pH=3-4 by slowaddition of 6N HCl, to afford a heterogenous mixture. The mixture wasfiltered and a white solid set aside. The aq. layer was furtherextracted with EtOAc and DCM. The combined organic layers dried weredried over MgSO₄, filtered and concentrated in vacuo. The resultantlight brown solid was triturated in EtOAc/EtOH (1:1) and filtered toafford a first crop of white solid product, which was set aside. Thefiltrate was again concentrated in vacuo. The residue was diluted withEtOAc, sonicated, treated with hexanes, and filtered. The process wasrepeated. The isolated solid product crops were dried under vacuum (3 h)and collected as 1.33 g (80%). LCMS E-S (M+H): 254.3 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.46 (d, 6H), 2.60 (s, 3H), 5.10 (quin, J=6.63 Hz, 1H),7.50 (s, 1H), 14.17 (br. s., 1H).

Intermediate 76-Chloro-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

1-(1,1-Dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (5.07 g, 20.34 mmol) and phosphorus oxychloride (28.4 ml, 305 mmol)were heated at 100° C. for 16 hours. The contents were concentrated invacuo. The residue was added to ice water followed by 1N NaOH untilbasic (pH>10). After stirring for 15 minutes, the mixture was adjustedto pH 3-4 by addition of 1N HCl. The contents were extracted with EtOAc,then washed with water, brine and concentrated in vacuo. The crudeproduct was purified by reverse phase HPLC (40-70% ACN/H₂O, 0.1% TFA).The product was collected as a solid, 0.50 g (9%). LCMS E-S (M+H)=268.3¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73 (s, 9H), 2.56 (s, 3H), 7.48 (s,1H), 14.17 (br. s., 1H).

Intermediate 8 3-(Aminomethyl)-4,6-dimethyl-2(1H)-pyridinonehydrochloride

Sodium acetate (10.24 g, 124.8 mmol), 10% palladium on carbon (1.08 g)and platinum oxide (76 mg) were placed in a dried Parr bottle undernitrogen, and a small amount of acetic acid was added to wet thecatalysts. A solution of4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (10 g, 67.6 mmol)in acetic acid was added to the Parr bottle followed by additionalacetic acid. The bottle was capped, placed on Parr apparatus, and shakenunder an atmosphere of hydrogen (45 psi) for 12 h. The reaction mixturewas filtered. The solvent was removed to give a residue, which wasdried. After addition of 50 mL of conc. HCl, the formed solids werefiltered. The yellow filtrate was concentrated and dried, followed byaddition of 10 mL conc. HCl, and 50 mL of EtOH. The mixture was storedat ca. 0° C. (i.e. freezer) for 2 h. The formed solids were filtered andwashed with cold EtOH, and dried to give the product as an HCl salt (39g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.85 (br. s., 1H) 8.13 (br.s., 3H) 5.93-6.01 (m, 1H) 3.72-3.80 (m, 2H) 2.22 (s, 3H) 2.16 (s, 3H).

Intermediate 93-(Aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone

To a dried 500 mL Parr bottle equipped with nitrogen inlet were placedsodium acetate (1.502 g, 18.30 mmol), 10% palladium on carbon (1.579 g,0.742 mmol), platinum(IV) oxide (0.011 g, 0.049 mmol) and a small amountof acetic acid to wet the catalysts under nitrogen stream. Next added2-hydroxy-6-methyl-4-(trifluoromethyl)-3-pyridinecarbonitrile (2.0 g,9.89 mmol) followed by acetic acid (175 mL) while under nitrogenatmosphere. The contents were sealed, placed on a Parr shaker, andreacted at 40 psi of H₂ for ca. 6 hr., keeping the H₂ psi between 20 and40 psi (vessel was refilled twice). The vessel was purged with nitrogenand the reaction mixture filtered through Celite, and the filter pad wasfurther washed with a small amount of acetic acid. The volatiles wereremoved in vacuo to afford a residue, which was dried under hi-vacuumfor 45 min. The solid was suspended in conc. HCl (12 mL), stirred, andfiltered (removed NaCl). The clear filtrate was concentrated in vacuoand the residue dried under hi-vacuum. The collected solid was suspendedin conc. HCl (2 mL) and diluted with EtOH (13 mL). The contents wereagitated (i.e. spatula) and stored at ca. 0° C. (i.e. freezer) for 30min to give a white solid. The solid was filtered and washed with coldethanol (5 mL). The solid was filtered and dried in vacuum oven for 1 h.The final product was collected as 0.95 g (40%). LCMS E-S (M+H)=206.9.¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H), 3.87 (d, J=5.05 Hz, 2H),6.41 (s, 1H), 8.12-8.37 (m, 3H).

Intermediate 10 3-(Aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone

Step 1

To a stirred suspension of CrCl₂ (58 g, 472.8 mmol in THF (1500 mL) wasadded a THF solution (500 mL) of 1,1-dichloro-2-propanone (10 g, 78.8mmol) and cyclohexanecarbaldehyde (8.84 g, 78.8 mmol). The reactionmixture was heated at reflux for 2 h, and then quenched by the additionof 1.0 M HCl. The reaction mixture was filtered through a pad of Celiteand concentrated in vacuo. The crude residue (10 g) was added to asolution of DMSO (150 mL) containing t-BuOK (7.5 g, 65.7 mmol), andcyanoacetamide (6.1 g, 72.3 mmol) and stirred at room temperature for 30min. Additional t-BuOK (22.5 g, 197.1 mmol) was added and the reactionmixture was stirred under an atmosphere of oxygen for an additional 1 h.The contents were purged with argon, diluted with 4 volumes of H₂O, andthen 5 volumes of 4 N HCl, which were added slowly. The reaction mixturewas filtered, washed with water and dried to give4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as 4.5 g(32%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.25 (s, 1H), 2.61-2.65 (m, 1H),2.22 (s, 3H), 1.66-1.79 (m, 4H), 1.24-1.46 (m, 6H).

Step 2

To an ice-bath cooled THF (100 mL) solution of the product from step 1(2 g, 9.26 mmol) were added NaBH₄ (0.81 g, 21.3 mmol), and I₂ (2.3 g,9.26 mmol), and the mixture stirred for 30 min. The reaction mixture wasthen heated at reflux for 3 h, and then allowed to cool to roomtemperature. After cooling to 0° C., the reaction mixture was acidifiedby slow addition of 3N HCl (1 mL). The reaction mixture was concentratedin vacuo and the crude product purified by reverse phase HPLC to givethe title compound as a solid (TFA salt), 0.5 g (25%). LCMS E-S(M+H)=221.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.8-11.9 (br s, 1H),7.80-7.93 (br s, 3H), 6.07 (s, 1H), 3.69 (s, 2H), 2.67-2.75 (m, 1H),2.17 (s, 3H), 1.58-1.72 (m, 5H), 1.19-1.41 (m, 5H).

Intermediate 11 3-(Aminomethyl)-4-cyclopropyl-6-methyl-2(1H)-pyridinonehydrochloride

The title compound was prepared in the same manner as described forintermediate 10 (step 2) from4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (5 g,28.7 mmol). The product was collected as a TFA salt, 0.50 g. LCMS E-S(M+H)=179.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.76-11.78 (br s, 1H),7.82-7.92 (br s, 3H), 5.61 (s, 1H), 3.94-3.99 (m, 2H), 2.11 (s, 3H),1.98-2.05 (m, 1H), 0.95-1.01 (m, 2H), 0.74-0.79 (m, 2H).

Intermediate 12 3-(Aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone

Step 1

To a solution of DMSO (300 mL) containing t-BuOK (20 g, 178 mmol) andcyanoacetamide (16.5 g, 196 mmol) was added (3E)-3-hepten-2-one (20 g,178 mmol), and contents stirred at room temperature for 30 min.Additional t-BuOK (60 g, 534 mmol) was added and the reaction mixturewas under an atmosphere of oxygen for an additional 1 h. The reactionmixture was purged with argon, diluted with 4 volumes of H₂O, and then 5volumes of 4 N HCl, which were added slowly. The reaction mixture wasfiltered, washed with water, and dried to give the product as 10 g(32%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.25-12.40 (br s, 1H), 6.18 (s,1H), 2.53 (t, 2H), 2.22 (s, 3H), 1.57-1.64 (m, 2H), 0.84 (t, 3H).

Step 2

The title compound was prepared in the same manner as described forintermediate 10 (step 2) from the product of step 1 (2 g, 11.2 mmol).The product was collected as 1.2 g (60%). LCMS E-S (M+H)=181.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.85-7.95 (br s, 3H), 5.99 (s, 1H), 3.80-3.85(m, 2H), 2.42 (t, 2H), 2.14 (s, 3H), 1.43-1.49 (m, 2H), 0.86 (t, 3H).

Intermediate 13 3-(Aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone

The title compound was prepared in the same manner as described forintermediate 12 (steps 1 and 2) from (3E)-4-phenyl-3-buten-2-one (20 g,137 mmol). The crude nitrile intermediate was obtained as 10 g (35%), ofwhich 4 g of this putative intermediate was converted to the titlecompound 1.2 g as a TFA salt. LCMS E-S (M+H)=215.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.2-12.3 (br s, 1H), 7.88-8.00 (br s, 3H), 7.43-7.51 (m,3H), 7.29-7.38 (m, 2H), 6.08 (s, 1H), 3.67-3.70 (m, 2H), 2.23 (s, 3H).

Intermediate 143-(Aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone

The title compound was prepared in the same manner as described forintermediate 12 (steps 1 and 2) from (3E)-5-methyl-3-hexen-2-one (20 g,137 mmol). The crude nitrile intermediate was obtained as 7 g (22%), ofwhich 3 g of this putative intermediate was converted to the titlecompound 1.3 g as a TFA salt. LCMS E-S (M+H)=181.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.8-11.9 (br s, 1H), 7.86-7.96 (br s, 3H), 6.10 (s, 1H),3.82-3.86 (m, 2H), 3.02-3.09 (m, 1H), 2.17 (s, 3H), 1.08 (d, 6H).

Intermediate 15 3-(Aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone

Step 1

To a solution of NaNH₂ (32.5 g, 862 mmol) in anhydrous ether (500 mL) at30° C. was added dropwise a mixture of butyric acid ethyl ester (50 g,431 mmol) and acetone (37.5 g 646.5 mol). After addition, the reactionmixture was stirred for 4 h. The reaction mixture was poured onto icewater with stirring. Additional ether was added, and the layers wereseparated. The aqueous layer was acidified to pH 5.0 with 2 N HCl andthen to pH 7.5 with Na₂CO₃. The aq. layer was then extracted with ether.The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude product (20 g, 156 mmol) and2-cyanoacetamide (13.12 g, 156 mmol) were suspended in EtOH (160 mL) at75° C., followed by addition of piperidine (13.2 g, 156 mmol). Thecontents were stirred and heated at reflux for 1 h. The mixture wascooled to room temperature, and filtered. The collected solid wassuspended in water and stirred for 1 h. The mixture was filtered anddried to give 4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinecarbonitrile(11 g, 40%). LCMS E-S (M+H)=181.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.3-12.4 (br s, 1H), 6.25 (s, 1H), 3.64 (s, 3H), 2.50 (t, 2H), 1.63 (m,2H), 0.94 (t, 3H).

Step 2

Sodium acetate (3.5 g, 42.6 mmol), palladium on carbon (0.81 g) andplatinum oxide (0.1 g) were placed in a dried Parr bottle flushed withnitrogen, followed by addition of a small amount of acetic acid (to wetthe catalysts). A solution of4-methyl-2-oxo-6-propyl-1,2-dihydro-pyridine-3-carbonitrile (5 g, 28mmol) in acetic acid was added to the Parr bottle followed by additionalacetic acid (200 mL). The vessel was capped, placed on Parr apparatusand hydrogenated at 45 psi for 12 h. The reaction mixture was filteredand the filtrate concentrated in vacuo. The crude product was purifiedby preparative HPLC to afford the title compound (TFA salt) as 4.1 g.LCMS E-S (M+H))=181.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.8-11.9 (br s,1H), 7.83-7.88 (br s, 3H), 5.99 (s, 1H), 3.77-3.81 (m, 2H), 2.37 (t,2H), 1.53 (m, 2H), 0.83 (t, 3H).

Intermediate 16 3-(Aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinone

Step 1 1-Cyclopropyl-1,3-butanedione

To a a stirring solution of THF (100 mL) was suspended potassiumtert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropylmethyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in30 mL THF at 35° C., via addition funnel over a 25 min period. Thecontents were heated and stirred at 60° C. After 3 h, the contents wereremoved from heating, and allowed to stir with cooling to roomtemperature. The reaction mixture was carefully diluted with 30 mL 2NHCl and stirred for 10 min. The mixture was extracted with diethyl ether(3×50 mL), and the combined organic layers washed with brine (1×50 mL).The organic layer was dried over MgSO₄, filtered, and concentrated invacuo. The crude oil was chromatographed on silica gel (eluent: 0 to 15%EtOAc in hexanes) with good separation to afford the desired product asa light yellow colored oil, 3.9 g in ˜75% purity (residual solvent), foran overall yield of 70%. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89-0.96(m, 2H), 1.09-1.15 (m, 2H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s,1H), 15.5-16.0 (br s, 1H).

Step 2 6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

To a stirring solution of ethanol (5 mL) were suspended1-cyclopropyl-1,3-butanedione (505 mg, 3.00 mmol) and cyanoacetamide(252 mg, 3.00 mmol), and the heterogenous contents heated untilhomogenous (ca. 75° C.). Next added piperidine (0.395 mL, 4.00 mmol),and the mixture was stirred with warming at reflux for 30 min. Thereaction mixture was allowed to cool to room temperature, whereinprecipitation ensued. The solid precipitate was filtered and set aside.The filtrate was concentrated in vacuo, and the oily residue treatedwith minimal EtOAc and then 10 mL hexanes to afford a 2nd crop of solid.The solid product crops were combined, suspended in water (7 mL),vigorously stirred, and vacuum filtered to afford a nearly white solidas 380 mg (73%). LCMS E-S (M+H)=175.1. ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.01-1.09 (m, 2H), 1.28 (dd, J=8.59, 2.27 Hz, 2H), 1.95-2.01 (m,1H), 2.43 (s, 3H), 5.82 (s, 1H).

Step 31,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate

6-Cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.35 g,2.01 mmol) was added to methanol (20 mL) and the stirring contentscooled to −10° C. Next added di-tert-butyloxycarbonyl (0.933 mL, 4.02mmol) and the suspension was stirred for 15 min. Next added inNiCl₂-6H₂O (0.055 g, 0.201 mmol) as a solid and stirred for 5 min. Nextadded NaBH₄ (0.532 g, 14.06 mmol) in 6 portions with 5 min. incrementsbetween each portion. After completed addition (ca. 30 min), the icebath was removed and the contents were stirred with warming to roomtemperature overnight. The reaction mixture was returned to −10° C.,followed by addition of 3 more portions of NaBH₄ (0.532 g, 14.06 mmol).The ice bath was removed and the mixture stirred at room temperature for1 h. The contents were quenched by addition of diethylethylene amine(0.218 mL, 2.01 mmol) and stirred for 45 min. at room temperature. Thevolatiles were removed in vacuo and the residue suspended in EtOAc andsat. NaHCO₃. The organic layer was washed with additional NaHCO₃. Thelayers were separated, and the organic layer dried over MgSO₄, filtered,and concentrated in vacuo. The crude product was purified by silica gelchromatography (eluent: 10% Methanol in Dichloromethane). The collectedproduct was dried under hi-vacuum for 1 h, and then treated with etherand filtered. After drying in vacuum oven at 45° C. for 2 h, the productwas collected as 0.28 g (50%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.73-0.80(m, 2H), 0.88-0.96 (m, 2H), 1.36 (s, 9H), 1.70-1.82 (m, 1H), 2.11 (s,3H), 3.95 (d, J=5.31 Hz, 2H), 5.66 (s, 1H), 6.51 (t, J=4.80 Hz, 1H),11.50 (br. s., 1H).

Step 4 3-(Aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinonehydrochloride

1,1-Dimethylethyl[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]carbamate(0.28 g, 1.006 mmol) was added to EtOAc (9 mL) and methanol (1.0 mL).The suspension was stirred at room temperature for 5 min., followed byaddition of 4M HCl in dioxane (5.03 mL, 20.12 mmol), and the contentswere stirred at room temperature overnight. The volatiles were thenremoved in vacuo to afford a solid. The solid was triturated with ether,filtered, and dried in a vacuum oven at 45° C. for 4 h. The titlecompound was collected as 0.22 g (100% yield). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 0.78-0.86 (m, 2H), 0.95-1.03 (m, 2H), 1.83 (tt, J=8.46, 5.05 Hz,1H), 2.16-2.22 (m, 3H), 3.75 (q, J=5.47 Hz, 2H), 5.79 (s, 1H), 8.02 (br.s., 3H), 11.92 (br. s., 1H).

Example 16-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Chloro-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid(0.12 g, 0.501 mmol), 1-hydroxy-7-azabenzotriazole (0.102 g, 0.751mmol), EDC (0.144 g, 0.751 mmol), and3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.123 g, 0.651 mmol) weredissolved in dimethyl sulfoxide (3.0 mL) and stirred at roomtemperature. Added next to the stirring contents was N-methylmorpholine(0.220 mL, 2.003 mmol) via syringe at once. After stirring at roomtemperature overnight, the reaction mixture was slowly added to water(75 mL) and stirred for 10 min. After sitting for 10 min. at roomtemperature, the contents were filtered to afford a tan solid which waswashed with water and then cold 50% aq EtOH. The contents were filtered,air-dried for 10 min., and then dried under vacuum for 1 hr. Thecollected solid was then further dried in a vacuum oven at 45° C. for 4hr. The title compound was collected as 0.105 g (55%). LCMS E-S(M+H)=373.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (d, J=6.82 Hz, 6H),2.13 (s, 3H), 2.20 (s, 3H), 4.35 (d, J=4.80 Hz, 2H), 5.07-5.20 (m, 1H),5.89 (s, 1H), 7.66 (s, 1H), 8.39 (s, 1H), 8.91 (t, J=4.80 Hz, 1H), 11.55(s, 1H).

Example 26-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 17 using6-chloro-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (486.6 mg, 1.92 mmol),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl (489 mg, 2.59 mmol),1-hydroxy-7-azabenzotriazole (392 mg, 2.88 mmol), N-methylmorpholine(0.84 ml, 7.67 mmol) and EDC (552 mg, 2.88 mmol). An additional 10 mLDMSO was added to the reaction mixture to facilitate stirring, and 10%K₂CO₃ was used instead of 50% aq. NaOH during the work up. LCMS E-S(M+H)=388.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (d, 6H), 2.12 (s, 3H),2.22 (s, 3H), 2.40 (s, 3H), 4.34 (d, J=5.05 Hz, 2H), 5.05 (quin, J=6.63Hz, 1H), 5.88 (s, 1H), 7.16 (s, 1H), 8.78 (t, J=4.93 Hz, 1H), 11.53 (br.s., 1H).

Example 36-Chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a solution of6-chloro-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (320 mg, 1.195 mmol) in DMSO (7 mL) were added3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (338 mg, 1.793 mmol),N-methylmorpholine (0.526 mL, 4.78 mmol), 1-hydroxy-7-azabenzotriazole(325 mg, 2.391 mmol) and EDC (458 mg, 2.391 mmol), and the reactionmixture was stirred overnight. The reaction mixture was quenched withwater (20 mL) and stirred for 10 min. The precipitate was collected byfiltration and further dried under high vacuum to give the product as asolid, 450 mg (94%). LCMS E-S (M+H)=402.1. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.71 (s, 9H), 2.12 (s, 3H), 2.22 (s, 3H), 2.37 (s, 3H), 4.33 (d,J=4.80 Hz, 2H), 5.88 (s, 1H), 7.09-7.21 (m, 1H), 8.77 (t, J=4.93 Hz,1H), 11.53 (s, 1H).

Example 4N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyloxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.15 g, 0.401 mmol), 4-pyridinol (0.057 g, 0.602 mmol), cesiumcarbonate (0.261 g, 0.802 mmol), and 1-(2-pyridinyl)-2-propanone (10.85mg, 0.080 mmol) were sequentially dissolved in DMSO (4.0 mL). Next addedcopper(I) bromide (5.76 mg, 0.040 mmol) and the suspension was stirredunder nitrogen (degassed) for 1 min. The sealed reaction mixture wasstirred with heating at 110° C. (heating block) for 20 h, and thenallowed to cool to room temperature overnight. The reaction mixture wasdiluted with EtOAc (25 mL) and water. The contents were vigorouslystirred and then filtered through Celite, washing the filter pad with20% THF/EtOAc. The layers were separated and the aq. layer extractedwith EtOAc. The combined organic layers were dried over MgSO₄, filtered,and concentrated in vacuo to a dark residue that was dried underhi-vacuum overnight. The crude product was purified by silica gelchromatography (eluent: gradient of 5-95% Dichloromethane/Chloroformcontaining 2M Ammonia (in methanol). The collected product was washedwith MTBE, filtered, and dried in a vacuum oven at 45° C. for 5 hr. Thefinal product was collected as 0.075 g (42%). LCMS E-S (M+H)=433.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (d,J=6.57 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=5.05 Hz, 2H),5.18-5.30 (m, 1H), 5.91 (s, 1H), 6.30-6.40 (m, 2H), 7.91 (s, 1H), 8.41(s, 1H), 8.57-8.65 (m, 2H), 8.92 (t, J=4.93 Hz, 1H), 11.58 (s, 1H).

Example 5N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.25 g, 0.669 mmol) was suspended in ethanol (4 mL) followed byaddition of allylamine (0.753 mL, 10.03 mmol). The sealed contents wereheated (heat block) at 140° C. for ca. 60 h, and then allowed to cool toroom temperature. The reaction mixture was diluted with water (100 mL)and then filtered. The collected solid was washed with additional waterand then dried in vacuum oven at 45° C. for 18 h. The final product wasisolated as an off-white solid, 0.225 g (83%). LCMS E-S (M+H)=394.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.42 (d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.21(s, 3H), 4.00 (t, J=5.43 Hz, 2H), 4.32 (d, J=5.05 Hz, 2H), 4.94 (quin,J=6.69 Hz, 1H), 5.09 (dd, J=10.36, 1.77 Hz, 1H), 5.18-5.29 (m, 1H),5.85-6.01 (m, 2H), 6.68 (s, 1H), 7.37 (t, J=5.56 Hz, 1H), 7.84 (s, 1H),8.45 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).

Example 66-Amino-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

A mixture of 10% Pd/C (0.200 g, 0.188 mmol) andN-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.200 g, 0.507 mmol) was suspended in ethanol (10 mL) and stirred.Added next was methanesulfonic acid (0.033 mL, 0.507 mmol), and thestirring contents were heated at reflux for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with DCM and filteredthrough Celite. The filter pad was washed with 10% MeOH/DCM. Thefiltrate was pre-adsorped onto silica gel, and the crude productpurified by silica gel chromatography (dry loaded, eluent: gradient of5-80% Dichloromethane/Chloroform containing 10% 2M Ammonia (inmethanol)). The collected product was dried in vacuum oven at 45° C.overnight. The final product was collected as 0.065 g (36%). LCMS E-S(M+H)=355.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (d, J=6.82 Hz, 6H),2.12 (s, 3H), 2.21 (s, 3H), 4.31 (d, J=5.05 Hz, 2H), 4.85-5.00 (m, 1H),5.89 (s, 1H), 6.49-6.68 (m, 3H), 7.85 (s, 1H), 8.46 (t, J=5.05 Hz, 1H),11.54 (br. s., 1H).

Example 76-Cyclopropyl-1-(1-methylethyl)-N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (167 mg, 0.680 mmol),3-(aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone trifluoroacetate (200mg, 0.680 mmol), HOAT (139 mg, 1.019 mmol), EDC (195 mg, 1.019 mmol),and N-methylmorpholine (0.299 mL, 2.72 mmol) were dissolved in DMF (6mL) and stirred at 40° C. for 24 h. The reaction mixture was poured intowater (20 mL) and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated to anorange oil. The residue was dissolved in DMSO, and purified by reversephase HPLC (mobile phase: 40-60% ACN in H₂O, 0.1% TFA). The isolatedproduct was dried in a vacuum oven overnight and furnished the TFA saltof the title compound as a white solid, 0.113 g (32%). LCMS E-S(M+H)=408.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.98 (m, 3H), 1.06 (d,J=7.07 Hz, 4H), 1.46 (d, J=6.82 Hz, 6H), 1.52-1.67 (m, 2H), 2.17-2.31(m, 4H), 2.37 (t, J=7.58 Hz, 2H), 4.36 (d, J=4.80 Hz, 2H), 5.02-5.27 (m,1H), 5.91 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.62-8.87 (m, 1H), 11.54(br. s., 1H).

Example 86-Cyclopropyl-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 7 from6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (250 mg, 1.019 mmol),3-(aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone.TFA (300 mg,1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (293 mg, 1.529 mmol),N-methylmorpholine (0.448 mL, 4.08 mmol), and DMF (6 mL), wherein thereaction time was 48 h. The final product was collected following abasic extraction (to remove residual starting material) as a whitesolid, 30 mg (7%). LCMS E-S (M+H)=408.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.95-1.16 (m, 10H), 1.38-1.54 (m, 6H), 2.16 (s 3H), 2.19-2.30 (m, 1H),3.12-3.29 (m, 1H), 4.29-4.48 (m, 2H), 5.03-5.21 (m, 1H), 6.03 (s, 1H),7.39 (s, 1H), 8.21 (s, 1H), 8.63-8.81 (m, 1H), 11.56 (s, 1H).

Example 91-(1-Methylethyl)-N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (192 mg, 0.680 mmol),3-(aminomethyl)-4-methyl-6-propyl-2(1H)-pyridinone.TFA (200 mg, 0.680mmol), HOAT (139 mg, 1.019 mmol), EDC (195 mg, 1.019 mmol), andN-methylmorpholine (0.299 mL, 2.72 mmol) were sequentially added to DMF(6 mL), and the mixture stirred at 40° C. overnight. The reactionmixture was then filtered. The collected solid was washed with ethanol,and dried, affording the final product as a white solid, 0.160 g (53%).LCMS E-S (M+H)=445.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.88 (t, 3H),1.46-1.65 (m, 8H), 2.24 (s, 3H), 2.38 (t, J=7.58 Hz, 2H), 4.43 (d,J=4.80 Hz, 2H), 5.37 (s, 1H), 5.93 (s, 1H), 8.23 (d, J=5.81 Hz, 2H),8.30 (s, 1H), 8.45 (s, 1H), 8.78 (d, J=5.31 Hz, 2H), 9.00 (br. s., 1H),11.56 (s, 1H).

Example 10N-[(6-Ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 9 from1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (403 mg, 1.427 mmol),3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone.TFA (400 mg, 1.427mmol), HOAT (291 mg, 2.141 mmol), EDC (1094 mg, 5.71 mmol),N-methylmorpholine (0.628 mL, 5.71 mmol), and DMF (6 mL). The finalproduct was collected as a white solid, 232 mg (38%). LCMS E-S(M+H)=432.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, 3H), 1.56 (d,J=6.57 Hz, 6H), 2.25 (s, 3H), 2.42 (q, J=7.41 Hz, 2H), 4.43 (d, J=4.55Hz, 2H), 5.29-5.45 (m, 1H), 5.93 (s, 1H), 8.22 (d, J=6.06 Hz, 2H), 8.30(s, 1H), 8.45 (s, 1H), 8.78 (d, J=5.81 Hz, 2H), 9.01 (t, J=4.55 Hz, 1H),11.58 (s, 1H).

Example 111-(1-Methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.531 mmol),3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (115 mg, 0.531 mmol),EDC (122 mg, 0.638 mmol), HOAt (72.3 mg, 0.531 mmol), andN-methylmorpholine (0.233 mL, 2.12 mmol) were suspended in DMF (5 mL)and stirred at room temperature overnight. water was added to thereaction mixture, and the contents were filtered. The filter cake waswashed with additional water (2×). The crude solid was purified byreverse phase HPLC (mobile phase: 10-30% ACN in H₂O, 0.1% TFA). Theisolated solid was then neutralized with saturated NaHCO₃, and washedwith EtOAc (5×15 mL). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo to afford the title compoundas an off-white solid, 0.060 g (24%). LCMS E-S (M+H)=445.3. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.84-0.92 (m, 3H), 1.47-1.54 (m, 2H), 1.57 (d,J=6.82 Hz, 6H), 2.14 (s, 3H), 2.48-2.52 (m, 2H), 4.42-4.49 (m, 2H),5.33-5.43 (m, 1H), 5.90-5.96 (m, 1H), 8.28-8.37 (m, 3H), 8.44-8.48 (m,1H), 8.82-8.87 (m, 2H), 8.99-9.04 (m, 1H), 11.58 (s, 1H).

Example 121-(1-Methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

A DMF solution (6 mL) of1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (288 mg, 1.019 mmol),3-(aminomethyl)-6-methyl-4-(1-methylethyl)-2(1H)-pyridinone.TFA (300 mg,1.019 mmol), HOAT (208 mg, 1.529 mmol), EDC (782 mg, 4.08 mmol), andN-methylmorpholine (0.448 mL, 4.08 mmol) was stirred overnight at 40° C.After cooling to room temperature, the reaction mixture was poured intoH₂O (50 mL) and EtOAc (50 mL). The aqueous layer was extracted withEtOAC (2×50 mL). The organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. The residue was dissolved in DMSOand purified by reverse phase (15-40% ACN in H₂O, 0.1% TFA). The productfractions were poured into sodium bicarbonate and extracted with ethylacetate. The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo to afford the title compound as a white solid (123mg, 27% yield). LCMS E-S (M+H)=445.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.10 (m, 6H), 1.56 (m, 6H), 2.17 (s, 3H), 3.17-3.28 (m, 1H), 4.45-4.56(m, 2H), 5.29-5.43 (m, 1H), 5.99-6.12 (m, 1H), 8.16-8.23 (m, 2H),8.24-8.29 (m, 1H), 8.40-8.46 (m, 1H), 8.71-8.82 (m, 2H), 8.96-9.04 (m,1H), 11.53-11.63 (m, 1H).

Example 136-Cyclopropyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 11 from1-(1-methylethyl)-6-(cyclopropyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.612 mmol). The product was collected as a white solid,0.043 g (16%). LCMS E-S (M+H)=408.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.89 (t, J=7.20 Hz, 3H), 1.06 (d, J=2.78 Hz, 3H), 1.08 (br. s., 1H),1.47 (d, J=6.57 Hz, 8H), 1.49-1.57 (m, 2H), 2.14 (s, 3H), 2.19-2.30 (m,1H), 4.38 (d, J=4.80 Hz, 2H), 5.03-5.18 (m, 1H), 5.92 (s, 1H), 7.40 (s,1H), 8.21 (s, 1H), 8.69-8.76 (m, 1H), 11.55 (s, 1H).

Example 141-(1-Methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 11 from1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.531 mmol) and3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (133 mg, 0.531 mmol).The product was collected as a white solid, 0.041 g (15%). LCMS E-S(M+H)=479.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57 (d, J=6.82 Hz, 6H)2.23 (s, 3H) 4.23-4.27 (m, 2H) 5.33-5.42 (m, 1H) 6.02-6.04 (m, 1H)7.35-7.42 (m, 1H) 7.43 (s, 4H) 8.23-8.26 (m, 1H) 8.34-8.39 (m, 2H)8.41-8.42 (m, 1H) 8.84-8.88 (m, 2H) 8.91-8.96 (m, 1H) 11.91 (s, 1H).

Example 15N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

A mixture of1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (169 mg, 0.6 mmol),3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone trifluoroacetate(221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780mmol), and N-methylmorpholine (0.264 mL, 2.400 mmol) in DMF (3 mL) werestirred at room temperature for 6 days. water (15 mL) was added to theslurry, and it was stirred for an hour. The precipitate was thencollected by vacuum filtration and rinsed with EtOH (4 mL), and thesolid was dried in the vacuum oven overnight to give the title compoundsas an off-white solid (137 mg, 45%). LCMS E-S (M+H)=485.2. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.09-1.44 (m, 5H), 1.56 (d, J=6.57 Hz, 6H),1.55-1.72 (m, 5H), 2.15 (s, 3H), 2.80-2.92 (m, 1H), 4.53 (d, J=4.55 Hz,2H), 5.36 (spt, J=6.53 Hz, 1H), 6.03 (s, 1H), 8.18-8.23 (m, 2H), 8.26(s, 1H), 8.45 (s, 1H), 8.75-8.82 (m, 2H), 9.01 (t, J=4.55 Hz, 1H), 11.59(s, 1H).

Example 16N-[(4-Cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 15 from6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (147 mg, 0.60 mmol),3-(aminomethyl)-4-cyclohexyl-6-methyl-2(1H)-pyridinone trifluoroacetate(221 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780mmol), N-methylmorpholine (0.264 mL, 2.400 mmol) and DMF (3 mL), whereinthe stir time was 3 d and the final product was not treated with EtOH.The final product was collected as 193 mg (68%). LCMS E-S (M+H)=448.4.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.11 (m, 4H), 1.15-1.43 (m, 5H),1.47 (d, J=6.57 Hz, 6H), 1.55-1.76 (m, 5H), 2.15 (s, 3H), 2.19-2.28 (m,1H), 2.83 (t, J=11.12 Hz, 1H), 4.45 (d, J=5.05 Hz, 2H), 5.12 (spt,J=6.69 Hz, 1H), 6.02 (s, 1H), 7.37 (s, 1H), 8.21 (s, 1H), 8.74 (t,J=4.80 Hz, 1H), 11.56 (s, 1H).

Example 176-Cyclopropyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 11 from1-(1-methylethyl)-6-(cyclopropyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.612 mmol) and3-(aminomethyl)-6-methyl-4-phenyl-2(1H)-pyridinone (153 mg, 0.612 mmol).The product was collected as a white solid, 0.067 g (24%). LCMS E-S(M+H)=442.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.11 (m, 3H), 1.47 (d,J=6.57 Hz, 5H), 2.22 (s, 3H), 2.24-2.29 (m, 1H), 3.17 (d, J=5.31 Hz,2H), 4.07-4.15 (m, 1H), 4.19 (d, J=4.29 Hz, 2H), 5.06-5.18 (m, 1H), 6.01(s, 1H), 7.36 (s, 1H), 7.38-7.49 (m, 5H), 8.18 (s, 1H), 8.70 (s, 1H),11.88 (s, 1H).

Example 18N-[(4-Cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

1-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (100 mg, 0.354 mmol),3-(aminomethyl)-4-cyclopropyl-6-methyl-2(1H)-pyridinone (104 mg, 0.354mmol), EDC (81 mg, 0.425 mmol), HOAt (48 mg, 0.354 mmol), andN-methylmorpholine (0.156 mL, 1.42 mmol) were suspended in DMF (5 mL)and stirred at room temperature overnight. The contents were filtered,washed with ethanol, and then concentrated in vacuo. The crude solid waspurified by reverse phase HPLC (mobile phase: 20-40%, ACN in H₂O, 0.1%TFA). The isolated solid was then neutralized with saturated NaHCO₃, andwashed with EtOAc (3×). The combined organic layers were dried overNa₂SO₄, filtered, and concentrated in vacuo to afford the title compoundas an off-white solid, 0.042 g (26%). LCMS E-S (M+H)=443.3. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.71-0.78 (m, 2H), 0.94 (dd, J=8.34, 2.27 Hz, 2H),1.57 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.13-2.18 (m, 1H), 4.62 (d,J=4.80 Hz, 2H), 5.38 (s, 1H), 5.54 (s, 1H), 8.37 (s, 1H), 8.44-8.54 (m,3H), 8.91 (d, J=6.06 Hz, 2H), 9.04 (s, 1H), 11.51 (br. s., 1H).

Example 196-Cyclopropyl-N-[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 4 mL solution of DMSO were sequentially added6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (0.11 g, 0.448 mmol),3-(aminomethyl)-6-cyclopropyl-4-methyl-2(1H)-pyridinone hydrochloride(0.106 g, 0.493 mmol), 1-hydroxy-7-azabenzotriazole (0.073 g, 0.538mmol), EDC (0.103 g, 0.538 mmol), and then N-methylmorpholine (0.197 mL,1.79 mmol) via syringe. After stirring overnight at room temperature,the suspension was diluted with 50 mL of water and stirred for 15 min.After standing at room temperature for 15 min., the reaction mixture wasfiltered and the collected solid washed with additional water. The solidwas then dried in a vacuum oven at 45° C. for 4 h. The product wasobtained as 0.165 g (89%). LCMS E-S (M+H)=406.5. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.76-0.82 (m, 2H), 0.91-0.98 (m, 2H), 1.03-1.12 (m, 4H),1.46 (d, J=6.82 Hz, 6H), 1.74-1.84 (m, 1H), 2.19 (s, 3H), 2.21-2.31 (m,1H), 4.34 (d, J=5.05 Hz, 2H), 5.05-5.18 (m, 1H), 5.73 (s, 1H), 7.42 (s,1H), 8.21 (s, 1H), 8.72 (t, J=4.93 Hz, 1H), 11.61 (br. s., 1H).

Example 20N-[(5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

A mixture of1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (169 mg, 0.60 mmol),3-(aminomethyl)-5-fluoro-4,6-dimethyl-2(1H)-pyridinone hydrochloride(136 mg, 0.660 mmol), EDC (150 mg, 0.780 mmol), HOAT (106 mg, 0.780mmol), and N-methylmorpholine (0.264 mL, 2.400 mmol) in DMF (3 mL) wasstirred at room temperature for 3 days. water (15 mL) was added to theslurry, and it was stirred for an hour. The precipitate was thencollected by vacuum filtration and rinsed with EtOH (4 mL), and thesolid was dried in the vacuum oven overnight to give the title compoundas 220 mg (76%). LCMS E-S (M+H)=435.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.56 (d, 7H), 2.18 (d, J=2.78 Hz, 3H), 2.25 (d, J=2.02 Hz, 3H), 4.45 (d,J=4.80 Hz, 2H), 5.37 (spt, J=6.65 Hz, 1H), 8.19-8.25 (m, 2H), 8.29 (s,1H), 8.44 (s, 1H), 8.74-8.81 (m, 2H), 9.07 (t, J=4.80 Hz, 1H), 11.66(br. s., 1H).

Example 21N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(ethylamino)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial equipped with stir bar, septum cap andnitrogen inlet were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(23 mg, 0.062 mmol) and ethanol (1 mL). Added next to the stirringsuspension was ethylamine (0.100 mL, 1.230 mmol) via syringe at once.The sealed reaction mixture was irradiated (microwave) at 110° C. for 40min, followed by addition of 0.1 mL ethylamine and further irradiationfor 7 hr at 130° C. After cooling to room temperature, about 50% of thevolatiles were removed by a stream of nitrogen. The reaction mixture wasdiluted with water (20 mL) and stirred for 10 min. The mixture was thenfiltered and the collected solid washed with water. The solid was driedin vacuum oven at 50° C. for 18 h, to afford the title compound as 0.17g (71%). LCMS E-S (M+H)=383.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t,J=7.07 Hz, 3H), 1.43 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.21 (s, 3H),3.35-3.39 (m, 2H), 4.31 (d, J=5.05 Hz, 2H), 4.89-5.01 (m, 1H), 5.89 (s,1H), 6.61 (s, 1H), 7.18 (t, J=5.31 Hz, 1H), 7.83 (s, 1H), 8.44 (t,J=5.05 Hz, 1H), 11.55 (br. s., 1H).

Example 22N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 50 mL round bottom flask fitted with a 3-way inlet was placed 10%Pd/C (0.071 g, 0.033 mmol) followed by degassing with N₂, and thenaddition of 2 mL ethanol. Added next to the stirring slurry was6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.25 g, 0.669 mmol). Additional ethanol (8 mL) and THF (10 mL) wereadded with slight warming to facilitate dissolution. The stirringcontents were allowed to cool (15 min.) then fitted with a balloon of H₂and allowed to stir at room temperature overnight. The contents werethen purged with N₂. The mixture was then diluted with 10% MeOH/DCM (20mL), stirred for 10 min., and filtered through Celite. The filtrate wasconcentrated in vacuo and the crude solid was triturated with ethanol.After filtration and washing the collected solid with additional ethanol(cold), the solid was air-dried for 15 min, then in vacuum oven at 40°C. overnight. The final product was collected as 185 mg (80%). LCMS E-S(M+H)=340.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (d, J=6.82 Hz, 6H),2.13 (s, 3H), 2.22 (s, 3H), 4.37 (d, J=4.80 Hz, 2H), 5.18-5.31 (m, 1H),5.89 (s, 1H), 7.54 (d, J=4.80 Hz, 1H), 8.36 (s, 1H), 8.63 (d, J=4.55 Hz,1H), 8.82 (t, J=4.93 Hz, 1H), 11.56 (s, 1H).

Example 236-Cyclopropyl-1-(1-methylethyl)-N-{[6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 19 from6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (0.12 g, 0.489 mmol), 1-hydroxy-7-azabenzotriazole (0.100 g, 0.734mmol), 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-2(1H)-pyridinone(0.154 g, 0.636 mmol, DMSO (3.0 mL), N-methylmorpholine (0.215 mL, 1.957mmol), and EDC (0.141 g, 0.734 mmol) The crude solid was purified bysilica gel chromatography (eluent: gradient 5-100% of 10% 2M NH₃ (inMeOH/DCM) and DCM) and the collected product dried in vacuum oven for 5h. The final product was collected as 0.112 g (50%). LCMS E-S(M+H)=434.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.12 (m, 4H), 1.47 (d,J=6.82 Hz, 6H), 2.20-2.33 (m, 4H), 4.34-4.54 (m, 2H), 5.12 (quin, J=6.63Hz, 1H), 6.33 (s, 1H), 7.39 (s, 1H), 8.18 (s, 1H), 8.70 (t, J=4.04 Hz,1H), 12.43 (s, 1H).

Example 246-(Dimethylamino)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 21 from6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(23 mg, 0.062 mmol), ethanol (0.7 mL), and dimethylamine (0.461 mL,0.923 mmol). The product was dried in vacuum oven at 50° C. for 5 hr andcollected as 0.016 g (67%). LCMS E-S (M+H)=383.3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.44 (d, J=6.57 Hz, 6H), 2.05-2.25 (m, 6H), 3.14 (s, 6H),4.34 (d, J=4.80 Hz, 2H), 4.99 (dt, J=13.39, 6.69 Hz, 1H), 5.89 (s, 1H),6.94 (s, 1H), 7.96 (s, 1H), 8.64 (t, J=4.93 Hz, 1H), 11.56 (br. s., 1H).

Example 25N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL reaction vial containing stir bar were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.060 g, 0.160 mmol), ethanol (1.5 mL), and then piperidine (0.318 mL,3.21 mmol) via syringe at once. The contents were capped, placed into aheat block, and heated at 120° C. for 18 h. After cooling to roomtemperature, the reaction mixture was diluted with water (40 mL),adjusted to pH 6-7, and stirred for 15 min. The contents were filteredand washed with water. The product was dried in vacuum oven at 50° C.for 5 hr. The product was obtained as 57 mg (82%). LCMS E-S (M+H)=422.8.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43 (d, J=6.82 Hz, 6H), 1.53-1.67 (m,6H), 2.12 (s, 3H), 2.20 (s, 3H), 3.61-3.73 (m, 4H), 4.34 (d, J=5.05 Hz,2H), 4.91-5.04 (m, 1H), 5.89 (s, 1H), 7.10 (s, 1H), 7.97 (s, 1H), 8.65(t, J=4.93 Hz, 1H), 11.51 (br. s., 1H).

Example 26N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-morpholinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL reaction vial containing stir bar were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.060 g, 0.160 mmol), ethanol (1.5 mL), and then morpholine (0.280 mL,3.21 mmol) via syringe at once. The contents were capped, placed into aheat block, and heated at 120° C. for 18 h and then at 135° C. for 2 hr.After cooling to room temperature, the reaction mixture was diluted withwater (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contentswere filtered and washed with water. The product was dried in vacuumoven at 50° C. for 5 hr. The product was obtained as 57 mg (79%). LCMSE-S (M+H)=425.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44 (d, J=6.57 Hz,6H), 2.12 (s, 3H), 2.19 (s, 3H), 3.56-3.66 (m, 4H), 3.69-3.78 (m, 4H),4.35 (d, J=4.80 Hz, 2H), 5.00 (quin, J=6.63 Hz, 1H), 5.89 (s, 1H), 7.13(s, 1H), 8.03 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.56 (br. s., 1H).

Example 27N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10-mL microwave vial were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.180mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine(71.1 mg, 0.235 mmol), DMSO (2.0 mL) and sodium carbonate (0.271 mL,0.541 mmol) and the mixture was degassed for 10 min under nitrogen.Bis(triphenylphosphine)palladium(II) chloride (10.13 mg, 0.014 mmol) wasadded and the contents were sealed. The mixture was irradiated(microwave) at 140° C. for 8 h. The reaction mixture was then quenchedwith water (5 mL) and filtered. The crude product was washed with water,dried, and then purified via silica gel chromatography (eluent: gradientof 0 to 15% (9:1 MeOH/NH₄OH)/DCM). The resulting product was treatedwith MeOH and 1N HCl. The mixture was concentrated in vacuo, dried underhigh vacuum and collected as the HCl salt, 42 mg (36%). LCMS E-S(M+H)=529.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (d, 6H), 2.13 (s, 3H),2.25 (s, 3H), 2.42 (s, 3H), 2.81 (d, J=4.55 Hz, 3H), 3.03-3.21 (m, 2H),3.41 (br. s., 2H), 3.52 (d, J=11.37 Hz, 2H), 4.39 (d, J=5.05 Hz, 2H),4.56 (d, J=14.40 Hz, 2H), 5.23 (quin, J=6.63 Hz, 1H), 5.91 (s, 1H), 7.19(d, J=9.09 Hz, 1H), 7.68 (s, 1H), 8.50 (dd, J=9.09, 2.27 Hz, 1H), 8.73(t, J=4.93 Hz, 3H), 8.98 (d, J=2.02 Hz, 3H), 10.97-11.21 (m, 2H)

Example 28N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1-piperazinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial equipped with stir bar were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.060 g, 0.160 mmol), ethanol (1.5 mL), and 1,1-dimethylethyl1-piperazinecarboxylate (0.299 g, 1.605 mmol). The stirring suspensionwas placed onto heat block and heated at 120° C. for 18 h, and thenirradiated (microwave) at 160° C. for 2 hr. The contents were cooled toroom temperature, diluted into water (40 mL), and then adjusted to pH6-7 and stirred for 15 min. The contents were filtered, washed withwater, and then dried in hi-vac oven at 50° C. for 5 hr. The collectedsolid (52 mg) was dissolved in CH₂Cl₂/TFA (3 mL, 2:1) and stirred atroom temperature for 2 hr. The volatiles were removed in vacuo to afforda residue which was then dissolved in CH₂Cl₂ and 10% 2M Ammonia (inmethanol) in Chloroform. The crude product was purified by silica gelchromatography (eluent: gradient of 10% 2M Ammonia (inMethanol/Chloroform) and Dichloromethane). The isolated solid was driedin vacuum oven at 45° C. for 18 hr. to afford the final product as 38 mg(55% yield). LCMS E-S (M+H)=423.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43(d, J=6.82 Hz, 6H), 2.08-2.24 (m, 6H), 2.75-2.89 (m, 4H), 3.53-3.64 (m,4H), 4.34 (d, J=4.80 Hz, 2H), 4.98 (quin, J=6.69 Hz, 1H), 5.89 (s, 1H),7.10 (s, 1H), 8.00 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.55 (br. s., 1H).

Example 29N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25mg, 0.080 mmol), DMSO (2.5 mL), triethylamine (0.112 mL, 0.802 mmol),and DBU (0.121 mL, 0.802 mmol). The suspension was stirred and degassedwith nitrogen for 5 min, forming an emulsion. Next added2-methyl-3-butyn-2-01 (0.194 mL, 2.006 mmol) and Pd(Ph₃P)₄ (0.046 g,0.040 mmol). The stirring contents were heated at 90° C. for 3 hr, andthen allowed to cool to room temperature. The reaction mixture waspoured into a solution of water and 20% THF/EtOAc, and stirred. Thelayers were separated, and the organic layer washed with brine. Theorganic layer was dried over MgSO₄, and then filtered through Celite,washing the filter pad with additional EtOAc. The filtrate wasconcentrated in vacuo and the crude residue dried overnight on a hi-vacpump. The crude product was purified by silica gel chromatography(eluent: gradient: 5-80% of DCM and Chloroform containing 10% 2M Ammonia(in methanol)). The collected product was dried in vacuum oven at 45° C.overnight, to afford the final product as 0.116 g (67% yield). LCMS E-S(M+H)=421.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.55 (m, 12H), 2.13(s, 3H), 2.20 (s, 3H), 4.35 (d, J=4.80 Hz, 2H), 5.15-5.26 (m, 1H), 5.70(s, 1H), 5.89 (s, 1H), 7.65 (s, 1H), 8.38 (s, 1H), 8.93 (t, J=4.80 Hz,1H), 11.55 (s, 1H).

Example 30N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-methyl-1H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.12 g, 0.321 mmol), 1,1-dimethylethyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.138 g, 0.385 mmol), potassium phosphate (tribasic) (0.204 g, 0.963mmol), 1,4-dioxane (3 mL), and water (0.75 mL). The stirring suspensionwas degassed with nitrogen for 10 min., wherein an emulsion had formed.Next added PdCl₂(dppf)-CH₂Cl₂ adduct (0.039 g, 0.048 mmol) and thecontents were placed onto a heat block and stirred at 105° C. overnight.After cooling to room temperature, the reaction mixture was diluted withEtOAc and filtered through Celite. The filter pad was washed with 50%THF/EtOAc. Silica gel was added to the combined filtrates and themixture concentrated in vacuo to a solid. The contents were purified bysilica gel chromatography (dry loaded, eluent: 5-80% gradient of DCM andchloroform containing 10% 2M Ammonia (in methanol)). The isolated solidwas dried in vacuum oven at 45° C. overnight to afford the final productas 0.126 g (81%). LCMS E-S (M+H)=470.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.56 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.25 (s, 3H), 2.60 (s, 3H), 4.43(d, J=5.05 Hz, 2H), 5.31-5.43 (m, 1H), 5.91 (s, 1H), 7.60 (d, J=8.84 Hz,1H), 8.22 (s, 1H), 8.29-8.37 (m, 2H), 8.60 (s, 1H), 8.97 (t, J=5.05 Hz,1H), 11.58 (br. s., 1H), 12.84 (s, 1H).

Example 31N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.125 g, 0.334 mmol), sodium iodide (10.02 mg, 0.067 mmol) and zinc(4.37 mg, 0.067 mmol), DMSO (2.5 mL), triethylamine (0.093 mL, 0.669mmol) and DBU (0.101 mL, 0.669 mmol). The stirring suspension wasdegassed with nitrogen for 5 min., wherein an emulsion had formed. Addednext were phenylacetylene (0.110 mL, 1.003 mmol) and Pd(Ph₃P)₄ (0.039 g,0.033 mmol). The sealed reaction mixture was placed onto a heat block,stirred at 90° C. for 3 hr, and then allowed to cool to room temperatureovernight. The contents were poured onto water and 20% THF/EtOAc,stirred, and the layers separted. The organic layer was washed withbrine, dried over MgSO₄, filtered, and concentrated in vacuo. The filterpad was washed with additional EtOAc. The combined filtrates wereconcentrated in vacuo to a yellow/orange residue that was dried onhi-vac pump. The crude solid was then pre-adsorbed onto silica gel andpurified by silica gel chromatography (dry loaded, eluent: 5-80%gradient of DCM and chloroform containing 10% 2M Ammonia (in methanol)).The isolated product was obtained as a yellow solid which was thenfurther purified by reverse phase HPLC (mobile phase: 20-90% ACN in H₂O,0.1% TFA, Gradient time: 8 min). The isolated solid was dissolved in 10%MeOH/CH₂Cl₂ and treated with 0.6 g of Silicycle carbonate resin for 30min. The contents were filtered through Celite and the filter pad washedwith additional 10% MeOH/CH₂Cl₂. The combined filtrates wereconcentrated in vacuo to afford a solid which was dried in vacuum ovenfor 18 hr. The final product was collected as 0.045 g (30%). LCMS E-S(M+H)=440.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51 (d, J=6.82 Hz, 6H),2.13 (s, 3H), 2.21 (s, 3H), 4.37 (d, J=4.80 Hz, 2H), 5.18-5.33 (m, 1H),5.90 (s, 1H), 7.45-7.56 (m, 3H), 7.64-7.73 (m, 2H), 7.86 (s, 1H), 8.42(s, 1H), 8.92 (t, J=4.80 Hz, 1H), 11.55 (br. s., 1H).

Example 32N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a suspension of palladium on carbon (0.063 g, 0.059 mmol) in ethanol(1 mL) under nitrogen was addedN-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.13 g, 0.295 mmol) and then ethanol (5 mL) and tetrahydrofuran (THF)(1.5 mL). The suspension was stirred under an atmosphere of hydrogen(ca. 1 atm, balloon) overnight. The reaction mixture was then evacuatedwith nitrogen, and diluted with 10% MeOH/DCM. Celite was added and thecontents stirred for 15 min., and then filtered through Celite(analytical grade) and washed with 10% MeOH/DCM. The filtrate wasconcentrated in vacuo and purified by silica gel chromatography (eluent:gradient of 5-95%. Dichloromethane/Chloroform containing 10% 2M ammonia(in methanol). The collected solid was dried in vacuum oven at 45° C.for 18 h. The final product was collected as 0.112 g (84%). LCMS E-S(M+H)=445.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46 (d, J=6.57 Hz, 6H),2.13 (s, 3H), 2.21 (s, 3H), 3.08-3.18 (m, 2H), 3.22-3.29 (m, 2H), 4.36(d, J=5.05 Hz, 2H), 5.18 (quin, J=6.69 Hz, 1H), 5.90 (s, 1H), 7.28 (d,J=6.06 Hz, 2H), 7.53 (s, 1H), 8.26 (s, 1H), 8.38-8.47 (m, 2H), 8.72 (t,J=5.05 Hz, 1H), 11.56 (s, 1H).

Example 33N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 31 from6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.15 g, 0.401 mmol), sodium iodide (0.012 g, 0.080 mmol), zinc (5.25mg, 0.080 mmol), DMSO (4.0 mL), triethylamine (0.168 mL, 1.204 mmol),DBU (0.121 mL, 0.802), 4-ethynylpyridine (0.112 g, 0.802 mmol), andPd(Ph₃P)₄ (0.046 g, 0.040 mmol). The crude product was purified bysilica gel chromatography (eluent: Gradient of 5-100% of DCM andchloroform containing 10% 2M Ammonia (in methanol)). The isolatedproduct was dried in vacuum oven for 18 hr. to afford the final productas 0.032 g (18%). LCMS E-S (M+H)=441.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.51 (d, J=6.57 Hz, 6H), 2.13 (s, 3H), 2.21 (s, 3H), 4.37 (d, J=4.80 Hz,2H), 5.20-5.32 (m, 1H), 5.90 (s, 1H), 7.62-7.69 (m, 2H), 7.93 (s, 1H),8.45 (s, 1H), 8.67-8.75 (m, 2H), 8.93 (t, J=4.80 Hz, 1H), 11.55 (s, 1H).

Example 34N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(phenylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.100 g, 0.267 mmol), cesium carbonate (0.305 g, 0.936 mmol),1,4-Dioxane (2.5 mL) and aniline (0.049 mL, 0.535 mmol). The stirringsuspension was degassed with nitrogen for 10 min. Added next were BINAP(0.033 g, 0.053 mmol) and palladium(II) acetate (6.01 mg, 0.027 mmol).The sealed mixture was stirred at 105° C. overnight. After cooling toroom temperature, the contents were poured onto EtOAc and filteredthrough Celite. The filter pad was washed with additional 50% THF/EtOAc.The combined filtrates were treated with silica gel and concentrated invacuo. The crude product was purified by silica gel chromatography (dryloaded, eluent: Gradient 5-80% of DCM and chloroform containing 10% 2MAmmonia (in methanol))). The isolated solid was dried in a vacuum ovenovernight and the final product collected as 0.061 g (52%). LCMS E-S(M+H)=431.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (d, J=6.57 Hz, 6H),2.13 (s, 3H), 2.23 (s, 3H), 4.35 (d, J=5.05 Hz, 2H), 4.98-5.11 (m, 1H),5.90 (s, 1H), 6.93-7.00 (m, 2H), 7.34 (t, J=7.96 Hz, 2H), 7.86 (d,J=7.58 Hz, 2H), 7.97 (s, 1H), 8.59 (t, J=5.05 Hz, 1H), 9.62 (s, 1H),11.58 (br. s., 1H).

Example 35N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(phenylmethyl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 10 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(0.100 g, 0.267 mmol), ethanol (2.0 mL) and then benzylamine (0.350 mL,3.21 mmol) via syringe at once. The sealed contents were irradiated at140° C. for 3 hr. The contents were transferred to a heat block andheated at 135° C. for 16 hr., and then at 145° C. for an additional 12h. After cooling to room temperature, the contents were diluted withCH₂Cl₂ and pre-absorbed onto silica gel. The crude product was purifiedby silica gel chromatography (dry loaded, eluent; gradient of 5-80% DCMand chloroform containing 10% 2M Ammonia (in methanol)). The isolatedsolid was triturated with MTBE, filtered, and washed with additionalMTBE. The collected solid was dried in vacuum oven at 45° C. overnightto afford the final product as 0.067 g (55%). LCMS E-S (M+H)=445.3. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.38 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.20(s, 3H), 4.31 (d, J=5.05 Hz, 2H), 4.56 (d, J=6.06 Hz, 2H), 4.92 (quin,J=6.69 Hz, 1H), 5.88 (s, 1H), 6.69 (s, 1H), 7.18-7.25 (m, 1H), 7.26-7.35(m, 2H), 7.35-7.43 (m, 2H), 7.77 (t, J=5.94 Hz, 1H), 7.83 (s, 1H), 8.47(t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).

Example 36N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid(60 mg, 0.27 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl(62 mg, 0.33 mmol) in DMSO (3 mL). 1-hydroxy-7-azabenzotriazole (56 mg,0.41 mmol) was added and the resulting mixture was degassed withnitrogen for 10 minutes. N-methylmorpholine (0.11 ml, 0.96 mmol) and EDC(79 mg, 0.41 mmol) were added, the vessel was sealed, and the lightbrown mixture was stirred at room temperature for 2 days. Next added 2mL of water and the mixture was stirred for 10 min. Solids thatprecipitated were sonicated, and allowed to stand at room temperaturefor 10 min. The contents were filtered, washed with water, and dried toafford the title compound (68 mg, 68%) as a light pink solid. LCMS E-S(M+H)=354.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.54 (s, 1H), 8.69 (t,J=4.80 Hz, 1H), 8.26 (s, 1H), 7.46 (s, 1H), 5.89 (s, 1H), 5.20 (quin,J=6.69 Hz, 1H), 4.36 (d, J=5.05 Hz, 2H), 2.63 (s, 3H), 2.21 (s, 3H),2.13 (s, 3H), 1.48 (d, J=6.57 Hz, 6H).

Example 37N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1,6-bis(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 52 using1,6-bis(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70mg, 0.28 mmol) to afford an off-white solid (95 mg, 86%). LCMS E-S(M+H)=382.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.56 (br. s., 1H, 8.76 (t,J=4.93 Hz, 1H), 8.26 (s, 1H), 7.50 (s, 1H), 5.90 (s, 1H), 5.15-5.25 (m,1H), 4.37 (d, J=5.05 Hz, 2H), 3.13-3.23 (m, 1H), 2.22 (s, 3H), 2.13 (s,3H), 1.50 (d, J=6.57 Hz, 6H), 1.32 (d, J=6.82 Hz, 6H).

Example 38N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid(70 mg, 0.25 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl(56.3 mg, 0.3 mmol) in DMSO (3 mL). 1-hydroxy-7-azabenzotriazole (51 mg,0.37 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. N-methylmorpholine (0.1 ml, 0.87 mmol) and EDC (72mg, 0.37 mmol) were added, the vessel was sealed, and the bright yellowmixture was stirred at room temperature for 2 days. Next added 2 mL ofwater, and the contents were stirred for 10 min. Solids thatprecipitated were sonicated, and allowed to stand at room temperaturefor 10 min. The reaction contents were filtered and washed with water.The solid was treated with 2 mL of EtOH, sonicated and heated, and thenallowed to cool to room temperature. The contents were filtered, washedwith water and dried to afford the title compound (74 mg, 70%) as awhite solid. LCMS E-S (M+H)=416.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58(s, 1H), 8.98 (t, J=4.80 Hz, 1H), 8.38 (s, 1H), 8.25-8.30 (m, 2H), 8.17(s, 1H), 7.49-7.59 (m, 3H), 5.91 (s, 1H), 5.30-5.38 (m, 1H), 4.42 (d,J=4.80 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.57 Hz, 6H).

Example 39N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(90 mg, 0.24 mmol), (4-fluorophenyl)boronic acid (33.7 mg, 0.24 mmol) in1,4-dioxane (3 mL). PdCl₂(dppf)-CH₂Cl₂ adduct (19.7 mg, 0.024 mmol) wasadded and the resulting mixture was degassed with nitrogen for 10 min.Sodium carbonate (77 mg, 0.72 mmol) was added, the vessel was sealed,and the mixture was heated at 85° C. for 2 hrs and then at 100° C.overnight. Added an additional 2 eq of boronic acid and 0.2 eq ofPdCl₂(dppf)-CH₂Cl₂ adduct. The contents were heated at 120° C. for 4 hr.and then irradiated (microwave) first at 160° C. for 90 min, and then at190° C. for 2 hrs. After cooling to room temperature, the solids werefiltered, washed with DMSO and the filtrate was evaporated. The crudeproduct was purified first by reverse-phase HPLC (C18, 5% to 80% CH₃CNin water with 0.1% TFA, 18 minute gradient) and then silica gelchromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Thecollected solid was dried to afford the title compound (13 mg, 12%) as awhite solid. LCMS E-S (M+H)=434.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58(br. s., 1H), 8.96 (t, J=4.67 Hz, 1H), 8.38 (s, 1H), 8.33 (dd, J=8.84,5.56 Hz, 2H), 8.16 (s, 1H), 7.40 (t, J=8.84 Hz, 2H), 5.91 (s, 1H), 5.33(dt, J=13.26, 6.76 Hz, 1H), 4.41 (d, J=4.55 Hz, 2H), 2.23 (s, 3H), 2.13(s, 3H), 1.55 (d, J=6.57 Hz, 6H).

Example 406-{4-[(Dimethylamino)sulfonyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(85 mg, 0.23 mmol) and {4-[(dimethylamino)sulfonyl]phenyl}boronic acid(104 mg, 0.46 mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(9.3 mg, 0.011 mmol) was added and the resulting mixture was degassedwith nitrogen for 10 min. Sodium bicarbonate (57.3 mg, 0.68 mmol) wasadded and the insoluble light brown mixture was heated in an oil bath at110° C. for 3 hrs. After cooling, 2 mL of water was added to the blackmixture and solids that precipitated were filtered. DMF was added alongwith a few drops of water and solids were filtered. DCM/MeOH (1:1) wasadded to the grey solids and they were filtered and dried to afford thetitle compound (69 mg, 57%) as a grayish solid. LCMS E-S (M+H)=523.2. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.59 (br. s., 1H), 9.01 (br. s., 1H), 8.51(m, J=8.34 Hz, 2H), 8.44 (s, 1H), 8.27 (s, 1H), 7.93 (m, J=8.34 Hz, 2H),5.91 (s, 1H), 5.36 (dt, J=13.14, 6.57 Hz, 1H), 4.43 (d, J=4.55 Hz, 2H),2.66 (s, 6H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, J=6.57 Hz, 6H).

Example 416-[6-(Dimethylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and [6-(dimethylamino)-3-pyridinyl]boronic acid (53.3mg, 0.32 mmol) in DME/water (3 mL:1 mL). PdCl₂ (dppf)-CH₂Cl₂ adduct (8.7mg, 0.011 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added,the vessel was sealed, and the insoluble green mixture was irradiated(microwave) at 150° C. for 20 min. After cooling, 2 mL of water wasadded to the dark green mixture and solids that precipitated werefiltered. EtOAc was added, the mixture was heated and some hexanes wereadded. Solids were filtered, dissolved in DCM/MeOH (1:1), and filteredthrough a pad of silica gel and the filtrate was evaporated. The residuewas dissolved in DCM and purified by SiO₂ chromatography (eluent:gradient of 0 to 90:10 DCM/MeOH) to afford a residual oil that wastriturated with EtOH/EtOAc (1:1). The resultant solid was filtered anddried to afford the title compound (46 mg, 45%) as a yellow solid. LCMSE-S (M+H)=460.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H), 9.02 (d,J=2.27 Hz, 1H), 8.87 (t, J=4.67 Hz, 1H), 8.36 (dd, J=8.84, 2.53 Hz, 1H),8.31 (s, 1H), 8.08 (s, 1H), 6.79 (d, J=8.84 Hz, 1H), 5.91 (s, 1H),5.25-5.34 (m, 1H), 4.40 (d, J=4.80 Hz, 2H), 3.12 (s, 6H), 2.23 (s, 3H),2.13 (s, 3H), 1.53 (d, J=6.57 Hz, 6H).

Example 42N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{4-[(methylamino)sulfonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(75 mg, 0.2 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (69 mg,0.32 mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.2 mg,0.01 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. Sodium bicarbonate (50.6 mg, 0.6 mmol) was added,the vessel was sealed, and the insoluble mixture was heated in amicrowave at 150° C. for 30 min. After cooling, 2 mL of water was addedto the mixture and solids that precipitated were filtered. DCM/MeOH(1:1) was added and the solution was filtered through a pad of silicagel and the filtrate was evaporated. The residue was purified by silicagel chromatography (eluent: gradient of 0 to 90:10 DCM/MeOH) and theisolated solid triturated in EtOAc. The solids were filtered and driedto afford the title compound (29 mg, 28%) as an off-white solid. LCMSE-S (M+H)=509.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (br. s., 1H),8.99 (t, J=4.93 Hz, 1H), 8.47 (m, J=8.59 Hz, 2H), 8.43 (s, 1H), 8.25 (s,1H), 7.95 (m, J=8.59 Hz, 2H), 7.60 (br. s., 1H), 5.91 (s, 1H), 5.36(quin, J=6.69 Hz, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.46 (s, 3H), 2.23 (s,3H), 2.13 (s, 3H), 1.56 (d, J=6.82 Hz, 6H).

Example 436-(4-Aminophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and (4-aminophenyl)boronic acid (44 mg, 0.32 mmol) inDME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.74 mg, 0.011 mmol)was added and the resulting mixture was degassed with nitrogen for 10min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel wassealed, and the insoluble light pink mixture was irradiated (microwave)at 150° C. for 30 min. After cooling, DCM/MeOH (1:1) was added, it waspre-absorbed on silica gel and purified by silica gel chromatography(eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). The isolated solid wastreated with MeOH. The solids that precipitated were filtered and driedto afford the title compound (63 mg, 66%) as a yellow solid. LCMS E-S(M+H)=431.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.56 (s, 1H), 8.88 (t,J=4.93 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.99 (d, J=2.02 Hz, 2H),6.69 (s, 1H), 6.67 (s, 1H), 5.90 (s, 1H), 5.61 (s, 2H), 5.24-5.32 (m,1H), 4.40 (d, J=4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.53 (s, 3H),1.51 (s, 3H).

Example 446-[4-(acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and [4-(acetylamino)phenyl]boronic acid (57.5 mg,0.32 mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.7 mg,0.010 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added,the vessel was sealed, and the insoluble light brown mixture was heatedat 110° C. for 2.5 h. After cooling, 2 mL of water was added to the darkgrey mixture and solids that precipitated were filtered. EtOAc wasadded, the mixture was heated and some hexanes were added. The solidswere filtered, dissolved in DCM/MeOH (1:1) and 1 mL of DMF. The contentswere pre-absorbed onto silica gel and purified by silica gelchromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Theisolated product was treated with MeOH, and the solids that precipitatedwere filtered, washed with hexanes and dried to afford the titlecompound (55 mg, 52%) as a white solid. LCMS E-S (M+H)=473.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 10.18 (s, 1H), 8.93 (t, J=4.93Hz, 1H), 8.35 (s, 1H), 8.22 (m, J=8.84 Hz, 2H), 8.13 (s, 1H), 7.76 (m,J=8.84 Hz, 2H), 5.91 (s, 1H), 5.28-5.37 (m, 1H), 4.41 (d, J=4.80 Hz,2H), 2.23 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 1.54 (d, J=6.82 Hz, 6H).

Example 456-(3-aminophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and (3-aminophenyl)boronic acid (46.9 mg, 0.34 mmol)in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.74 mg, 0.01 mmol)was added and the resulting mixture was degassed with nitrogen for 10min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added, the vessel wassealed, and the reaction mixture was irradiated (microwave) at 150° C.for 25 min. After cooling, 2 mL of water was added to the black mixtureand solids that precipitated were filtered. DCM/MeOH (1:1) was added,the mixture was pre-absorbed on silica gel and purified by silica gelchromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Theisolated product was treated with EtOH/EtOAc/hexanes (1:1:1). The solidsthat precipitated were filtered and dried to afford the title compound(40 mg, 42%) as a light grey solid. LCMS E-S (M+H)=431.3. ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.56 (br. s., 1H), 8.96 (t, J=4.93 Hz, 1H), 8.34(s, 1H), 8.02 (s, 1H), 7.46 (t, J=1.89 Hz, 1H), 7.36 (d, J=7.58 Hz, 1H),7.18 (t, J=7.71 Hz, 1H), 6.69 (dd, J=7.83, 1.52 Hz, 1H), 5.90 (s, 1H),5.25-5.37 (m, 3H), 4.40 (d, J=4.80 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H),1.55 (s, 3H), 1.54 (s, 3H).

Example 46N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{4-[(methylamino)carbonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 61 using {4-[(methylamino)carbonyl]phenyl}boronic acid (57.5 mg,0.32 mmol) to afford a light grey solid (70 mg, 68%). LCMS E-S(M+H)=473.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H), 9.00 (t,J=4.80 Hz, 1H), 8.59 (q, J=4.38 Hz, 1H), 8.41 (s, 1H), 8.35 (m, J=8.59Hz, 2H), 8.24 (s, 1H) 8.01 (m, J=8.59 Hz, 2H), 5.91 (s, 1H), 5.33-5.41(m, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.83 (d, J=4.55 Hz, 3H), 2.23 (s, 3H),2.13 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H).

Example 476-[3-(Acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and [3-(acetylamino)phenyl]boronic acid (57.5 mg,0.32 mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.7 mg,0.010 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added,the vessel was sealed and the reaction mixture was irradiated(microwave) at 150° C. for 30 min. After cooling, 2 mL of water wasadded and solids that precipitated were filtered. DCM/MeOH (1:1) wasadded, the mixture was pre-absorbed on silica gel and purified by silicagel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Theisolated product was treated with EtOH and DCM, filtered, and dried toafford the title compound (65 mg, 63%) as a white solid. LCMS E-S(M+H)=473.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H), 9.02 (t,J=4.80 Hz, 1H), 8.61-8.68 (m, 2H), 8.37-8.43 (m, 2H), 8.21 (s, 1H), 7.94(d, J=7.83 Hz, 1H), 7.65 (t, J=7.83 Hz, 1H), 5.91 (s, 1H), 5.37 (quin,J=6.63 Hz, 1H), 4.42 (d, J=4.80 Hz, 2H), 2.84 (d, J=4.29 Hz, 3H), 2.24(s, 3H), 2.13 (s, 3H), 1.57 (s, 3H), 1.55 (s, 3H).

Example 48N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)boronic acid (50 mg, 0.32mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct (8.74 mg,0.011 mmol) was added and the resulting mixture was degassed withnitrogen for 10 min. Sodium bicarbonate (53.9 mg, 0.64 mmol) was added,the vessel was sealed, and reaction mixture was heated in a microwave at150° C. for 30 min. After cooling, 2 mL of water was added to the blackmixture and solids that precipitated were filtered. DCM/MeOH (1:1) wasadded, the mixture was pre-absorbed on silica gel and purified by silicagel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Theisolated product was treated with EtOH/EtOAc (1:1) and sonicated. Thesolids that precipitated were filtered, washed with EtOH and DCM, anddried to afford the title compound (41 mg, 42%) as a light grey solid.LCMS E-S (M+H)=449.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H),11.52 (br. s., 1H), 11.47 (s, 1H), 8.75 (t, J=5.05 Hz, 1H), 8.36 (s,1H), 8.31 (s, 1H), 8.23 (s, 1H), 5.90 (s, 1H), 5.27 (quin, J=6.69 Hz,1H), 4.37 (d, J=5.05 Hz, 2H), 2.23 (s, 3H), 2.13 (s, 3H), 1.52 (s, 3H),1.50 (s, 3H).

Example 496-(2-Amino-4-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as example 48 using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (65.9 mg,0.3 mmol) to afford an off-white solid (60 mg, 73%). LCMS E-S(M+H)=432.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 8.99 (t,J=4.80 Hz, 1H), 8.41 (s, 1H), 8.05-8.13 (m, 2H), 7.24-7.32 (m, 2H), 6.14(s, 2H), 5.91 (s, 1H), 5.33 (quin, J=6.69 Hz, 1H), 4.41 (d, J=4.80 Hz,2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.55 (d, J=6.57 Hz, 6H).

Example 506-[4-(Aminosulfonyl)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as example 48 using[4-(aminosulfonyl)phenyl]boronic acid (64.5 mg, 0.32 mmol) to afford alight grey solid (76 mg, 74%). LCMS E-S (M+H)=495.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.58 (br. s., 1H), 8.99 (t, J=4.80 Hz, 1H), 8.41-8.48(m, 3H), 8.25 (s, 1H), 8.00 (d, J=8.59 Hz, 2H), 7.50 (s, 2H), 5.91 (s,1H), 5.37 (quin, J=6.69 Hz, 1H), 4.43 (d, J=4.80 Hz, 2H), 2.23 (s, 3H),2.14 (s, 3H), 1.56 (d, J=6.57 Hz, 6H).

Example 51N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{4-[(methylsulfonyl]amino]phenyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(75 mg, 0.2 mmol) and {4-[(methylsulfonyl)amino]phenyl}boronic acid(43.1 mg, 0.2 mmol) in DME/water (3 ml:1 ml). PdCl₂(dppf)-CH₂Cl₂ adduct(8.2 mg, 0.01 mmol) was added and the resulting mixture was degassedwith nitrogen for 10 min. Sodium bicarbonate (50.6 mg, 0.6 mmol) wasadded, the vessel was sealed, and the reaction mixture was irradiated(microwave) at 150° C. for 25 min. After cooling, 2 mL of water wasadded to the black mixture and solids that precipitated were filtered.DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel andpurified by silica gel chromatography (eluent: gradient 0 to 90:10:1DCM/MeOH/NH₄OH). The isolated product was suspended in EtOAc heated, andsonicated. Some hexanes was added and the contents allowed to cool toroom temperature. Solids that precipitated were filtered. The solid wasthen suspended in EtOH, heated, and sonicated. After cooling to roomtemperature, the solids were filtered and dried to afford the titlecompound (38 mg, 36%) as a beige solid. LCMS E-S (M+H)=509.0. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.57 (s, 1H), 10.05 (br. s., 1H), 8.93 (t,J=4.93 Hz, 1H), 8.35 (s, 1H), 8.24 (m, J=8.59 Hz, 2H), 8.11 (s, 1H),7.37 (m, J=8.84 Hz, 2H), 5.91 (s, 1H), 5.32 (quin, J=6.69 Hz, 1H), 4.41(d, J=4.80 Hz, 2H), 3.08 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (s,3H), 1.54 (s, 3H).

Example 526-{4-[(Dimethylamino)sulfonyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(75 mg, 0.19 mmol) andN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(90 mg, 0.29 mmol) in DME/water (3 ml:1 ml). PdCl₂ (dppf)-CH₂Cl₂ adduct(7.9 mg, 0.009 mmol) was added and the resulting mixture was degassedwith nitrogen for 10 min. Sodium bicarbonate (48.7 mg, 0.58 mmol) wasadded, the vessel was sealed, and the reaction mixture was irradiated(microwave) at 150° C. for 30 min. After cooling, 2 mL of water wasadded and solids that precipitated were filtered. DCM/MeOH (1:1) wasadded, the mixture was pre-absorbed on silica gel and purified by silicagel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). Theisolated product was treated with EtOH/EtOAc (1:1), the solids filteredand washed with EtOAc and DCM, and then dried to afford the titlecompound (83 mg, 78%) as a white solid. LCMS E-S (M+H)=537.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.54 (s, 1H) 8.79 (t, J=4.93 Hz, 1H) 8.47 (m,J=8.59 Hz, 2H) 7.90 (m, J=8.59 Hz, 2H) 7.80 (s, 1H) 5.89 (s, 1H) 5.28(quin, J=6.69 Hz, 1H) 4.40 (d, J=5.05 Hz, 2H) 2.66 (s, 6H) 2.47 (s, 3H)2.25 (s, 3H) 2.12 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H).

Example 53N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(60 mg, 0.16 mmol) and 4-piperidinamine (2 mL) in EtOH (3 mL). Thevessel was sealed and the reaction mixture was irradiated (microwave) at125° C. for 5 hr and then at 160° C. for 90 min. The mixture wasevaporated under vacuum and the resulting residue was partitionedbetween EtOAc and water. Organics were washed with water (2×) and brine,dried over MgSO₄, filtered and evaporated. The residue was purified bysilica gel chromatography (eluent: gradient 0 to 90:10:1DCM/MeOH/NH₄OH). The isolated product was treated with EtOAc/ether (1:1)and allowed to stand at room temperature overnight. The solids that hadprecipitated were triturated, filtered, and dried to afford the titlecompound as a pale yellow solid 25 mg (35%). LCMS E-S (M+H)=438.0. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.66 (t, J=4.67 Hz, 1H) 7.98 (s, 1H) 7.12(s, 1H) 5.89 (s, 1H) 4.98 (dt, J=13.33, 6.60 Hz, 1H) 4.30-4.41 (m, 4H)3.01 (t, J=11.62 Hz, 2H) 2.85 (br. s., 1H) 2.20 (s, 3H) 2.12 (s, 3H)1.80 (d, J=10.36 Hz, 2H) 1.44 (s, 3H) 1.43 (s, 3H) 1.18-1.30 (m, 3H)0.79-0.91 (m, 1H)

Example 54N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(60 mg, 0.16 mmol) and tetrahydro-2H-pyran-4-amine (2 ml, 19 mmol) inEtOH (3 mL). The vessel was sealed and the reaction mixture wasirradiated (microwave) at 125° C. for 2 hr. and then at 170° C. for 1hr. The mixture was concentrated to ca. 20% volume and NMP (2 mL) addedto the reaction mixture. The contents were again irradiated (microwave)first at 180° C. for 2.5 h and then at 190° C. for 75 min. The mixturewas evaporated under vacuum, and the resulting residue was purified bysilica gel chromatography (eluent: gradient 0 to 90:10:1DCM/MeOH/NH₄OH). The isolated product was treated with EtOAc/hexanes(1:1), sonicated, and heated. After cooling, solids that precipitatedwere filtered and dried to afford the title compound (46 mg, 64%) as anoff-white solid. LCMS E-S (M+H)=439.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.55 (s, 1H) 8.44 (t, J=5.05 Hz, 1H) 7.83 (s, 1H) 7.20 (d, J=7.33 Hz,1H) 6.63 (s, 1H) 5.89 (s, 1H) 4.93 (quin, J=6.69 Hz, 1H) 4.32 (d, J=5.05Hz, 2H) 3.99-4.06 (m, 1H) 3.88 (dt, J=11.49, 3.47 Hz, 2H) 3.45 (td,J=11.37, 2.02 Hz, 2H) 2.21 (s, 3H) 2.13 (s, 3H) 1.95 (d, J=10.61 Hz, 2H)1.41-1.51 (m, 8H).

Example 55N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(4-pyridinylmethyl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(60 mg, 0.16 mmol) and (4-pyridinylmethyl)amine (0.065 ml, 0.64 mmol) inEtOH (2 mL). The vessel was sealed and the reaction mixture was heatedat 90° C. overnight. An additional 1 mL of (4-pyridinylmethyl) amine wasadded and the mixture was heated in a microwave at 160° C. for 90 min.The EtOH solvent was removed under reduced pressure, 2 mL of NMP wasadded, and the mixture was then irradiated (microwave) at 180° C. for 90min. The mixture was evaporated under vacuum, and the resulting residuewas partitioned between EtOAc and water. The crude residue was extractedwith EtOAc, DCM and DCM/isopropanol (70:30). The combined organics werewashed with water (2×) and brine, dried over MgSO₄, filtered andevaporated. The residue was purified by silica gel chromatography(eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). The isolated yellow oilwas treated with EtOAc and sonicated. The filtered solid was washed withhexanes and dried to afford the title compound (26 mg, 36%) as a whitesolid. LCMS E-S (M+H)=446.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.56 (s,1H) 8.50 (t, J=5.18 Hz, 1H) 8.43-8.48 (m, 2H) 7.89 (t, J=5.94 Hz, 1H)7.84 (s, 1H) 7.34 (d, J=6.06 Hz, 2H) 6.73 (s, 1H) 5.89 (s, 1H) 4.83(quin, J=6.69 Hz, 1H) 4.58 (d, J=5.81 Hz, 2H) 4.32 (d, J=5.05 Hz, 2H)2.21 (s, 3H) 2.13 (s, 3H) 1.32 (d, J=6.82 Hz, 6H).

Example 566-{[2-(Dimethylamino)ethyl]amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and (2-aminoethyl)dimethylamine (37.7 mg, 0.43 mmol)in NMP (2 mL). The vessel was sealed and the reaction mixture wasirradiated (microwave) at 150° C. for 1 h. The mixture was evaporatedunder vacuum, and the resulting residue was partitioned between EtOAcand water. The contents were extracted with EtOAc, DCM andDCM/isopropanol (70:30). The combined organics were washed with water(2×) and brine, dried over MgSO₄, filtered and evaporated. The residuewas purified by silica gel chromatography (eluent: gradient 0 to 90:10:1DCM/MeOH/NH₄OH). The isolated yellow oil was treated with EtOAc andsonicated. Solids that precipitated were filtered, washed with hexanes,and dried to afford the title compound (60 mg, 65%) as a white solid.LCMS E-S (M+H)=425.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.55 (br. s., 1H)8.43 (t, J=5.05 Hz, 1H) 7.84 (s, 1H) 7.08 (t, J=5.05 Hz, 1H) 6.67 (s,1H) 5.89 (s, 1

H) 4.94 (quin, J=6.63 Hz, 1H) 4.32 (d, J=5.05 Hz, 2H) 3.44 (q, J=6.48Hz, 2H) 2.44 (t, J=6.69 Hz, 2H) 2.17-2.22 (m, 9H) 2.12 (s, 3H) 1.43 (d,J=6.57 Hz, 6H).

Example 57N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[(2-hydroxyethyl)amino]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

In a 25 mL sealable tube under nitrogen were combined6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and 2-aminoethanol (1 ml) in NMP (2 mL). The vesselwas sealed and the reaction mixture was irradiated (microwave) at 130°C. for 1 h and then at 140° C. for 90 min. The mixture was evaporatedunder vacuum and the residue was purified by silica gel chromatography(eluent: gradient 0 to 90:10:1 DCM/MeOH/NH₄OH). The isolated yellow oilwas treated with EtOAc, sonicated, and treated with hexanes. The solidswere filtered, dissolved in DMF (1 mL), and a few drops of water wereadded. The solution was allowed to stand at room temperature overnight,and then sonicated. The filtered solid was washed with Hexanes/EtOAc(1:1), and then dried to afford the title compound (55 mg, 63%) as alight yellow solid. LCMS E-S (M+H)=399.0. ¹H NMR (400 MHz, DMSO-d₆) δppm 11.56 (br. s., 1H) 8.44 (br. s., 1H) 7.84 (s, 1H) 7.20 (br. s., 1H)6.68 (s, 1H) 5.89 (s, 1H) 4.95 (dt, J=13.01, 6.38 Hz, 1H) 4.72 (t,J=4.93 Hz, 1H) 4.32 (d, J=4.80 Hz, 2H) 3.58 (d, J=5.56 Hz, 2H) 3.38-3.46(m, 2H) 2.21 (s, 3H) 2.12 (s, 3H) 1.43 (d, J=6.57 Hz, 6H)

Example 58N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[5-(methyloxy)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 20 mL microwave vial were sequentially added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(100 mg, 0.267 mmol,3-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(69.2 mg, 0.294 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (21.84 mg, 0.027 mmol),(DME) (5 mL), and water (2 mL). The reaction mixture was degassed withnitrogen for 5 min. Sodium bicarbonate (67.4 mg, 0.802 mmol) was addedand the contents sealed and irradiated (microwave) at 140° C. Thereaction mixture was cooled to room temperature and poured on a silicacolumn (through Na₂SO₄) and purified by silica gel chromatography(eluent: 5% MeOH/CH₂Cl₂) which provided the desired product as anoff-white solid after preciptation from EtOAc/MeOH. The final productwas collected as 0.090 g (76%). LCMS E-S (M+H) 447.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s., 1H), 9.06 (d, J=1.52 Hz, 1H), 8.92-9.00 (m,1H), 8.39-8.48 (m, 2H), 8.24 (s, 1H), 8.14 (d, J=1.77 Hz, 1H), 5.91 (s,1H), 5.30-5.45 (m, 1H), 4.42 (d, J=4.80 Hz, 2H), 3.97 (s, 3H), 2.24 (s,3H), 2.13 (s, 3H), 1.55 (d, J=6.82 Hz, 6H).

Example 59N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(methyloxy)-4-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 2-methoxypyridine-4-boronic acid pinacol ester (69.2mg, 0.294 mmol) to give the desired product as a grey solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.051 g (41%). LCMS E-S (M+H) 447.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (br. s., 1H) 9.00 (t, J=4.80 Hz, 1H) 8.44 (s, 1H)8.36 (s, 1H) 8.26 (s, 1H) 7.84 (dd, J=5.31, 1.52 Hz, 1H) 7.67 (s, 1H)5.91 (s, 1H) 5.32-5.40 (m, 1H) 4.42 (d, J=4.80 Hz, 2H) 3.94 (s, 3H) 2.23(s, 3H) 2.13 (s, 3H) 1.55 (d, 6H).

Example 606-(6-Amino-3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 6-aminopyridine-3-boronic acid pinacol ester (64.8 mg,0.294 mmol) to give the desired product as a grey solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.060 g (49%). LCMS E-S (M+H)=432.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (br. s., 1H) 8.85-8.92 (m, 2H) 8.31 (s, 1H) 8.26(dd, J=8.59, 2.53 Hz, 1H) 8.04 (s, 1H) 6.57 (d, J=8.59 Hz, 1H) 6.46 (s,2H) 5.90 (s, 1H) 5.25-5.33 (m, 1H) 4.40 (d, J=4.80 Hz, 2H) 2.22 (s, 3H)2.13 (s, 3H) 1.53 (d, 6H).

Example 61N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[5-(methylsulfonyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using [5-(methylsulfonyl)-3-pyridinyl]boronic acid (59.1 mg,0.294 mmol) to give the desired product as an off-white solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.079 g (59%). LCMS E-S (M+H)=495.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.59 (br. s., 1H), 9.76 (d, J=2.27 Hz, 1H), 9.21 (d,J=2.02 Hz, 1H), 9.00-9.06 (m, 2H), 8.46 (s, 1H), 8.37 (s, 1H), 5.91 (s,1H), 5.36-5.44 (m, 1H), 4.43 (d, J=4.80 Hz, 2H), 3.45 (s, 3H), 2.24 (s,3H), 2.13 (s, 3H), 1.56 (d, 6H).

Example 62N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2-furanyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using 2-(2-furanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(57.1 mg, 0.294 mmol) to give the desired product as an white solidafter evaporation and preciptation from EtOAc/MeOH. The final productwas collected as 0.049 g (44%). LCMS E-S (M+H) 406.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H) 8.93 (t, J=4.93 Hz, 1H) 8.33 (s, 1H) 7.97(s, 1H) 7.94 (d, J=1.01 Hz, 1H) 7.34 (d, J=2.78 Hz, 1H) 6.73 (dd,J=3.54, 1.77 Hz, 1H) 5.90 (s, 1H) 5.19-5.32 (m, 1H) 4.39 (d, J=4.80 Hz,2H) 2.23 (s, 3H) 2.13 (s, 3H) 1.52 (d, 6H).

Example 63N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[6-[(methylamino)carbonyl]-3-pyridinyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 2-(N-methylamidocarboxy)-5-pyridineboronic acid pinacolester (70.1 mg, 0.267 mmol) to give the desired product as an off-whitesolid after evaporation and preciptation from EtOAc/MeOH. The finalproduct was collected as 0.080 g (60%). LCMS E-S (M+H)=474.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.59 (br. s., 1H), 9.46 (d, J=1.52 Hz, 1H),8.98 (t, J=4.55 Hz, 1H), 8.85 (d, J=5.05 Hz, 1H), 8.78 (dd, J=8.21, 2.15Hz, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.20 (d, J=8.08 Hz, 1H), 5.91 (s,1H), 5.30-5.42 (m, 1H), 4.42 (d, J=4.55 Hz, 2H), 2.87 (d, J=4.80 Hz,3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.56 (d, 6H).

Example 646-[5-[(Cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 usingN-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]cyclopropanesulfonamide(95 mg, 0.267 mmol) to give the desired product as an off-white solidafter evaporation and preciptation from EtOAc/MeOH. The final productwas collected as 0.100 g (66%). LCMS E-S (M+H) 566.4. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H) 9.47 (s, 1H) 8.94 (t, J=4.93 Hz, 1H) 8.89(d, J=2.27 Hz, 1H) 8.49 (d, J=2.27 Hz, 1H) 8.37 (s, 1H) 8.15 (s, 1H)5.91 (s, 1H) 5.29 (m, 1H) 4.41 (d, J=4.80 Hz, 2H) 4.01 (s, 3H) 2.70-2.78(m, 1H) 2.23 (s, 3H) 2.13 (s, 3H) 1.56 (d, J=6.57 Hz, 6H) 0.91-1.00 (m,4H).

Example 65N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 usingN-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide(96 mg, 0.267 mmol) to give the desired product as an off-whitesolidafter evaporation and preciptation from EtOAc/MeOH. The final productwas collected as 0.050 g (33%). LCMS E-S (M+H)=572.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H), 10.83 (s, 1H), 9.10 (d, J=1.77 Hz, 1H),8.95 (t, J=5.05 Hz, 1H), 8.37-8.45 (m, 2H), 8.32 (t, J=2.15 Hz, 1H),8.17 (s, 1H), 7.82-7.91 (m, 2H), 7.55-7.69 (m, 3H), 5.90 (s, 1H),5.18-5.30 (m, 1H), 4.41 (d, J=5.05 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H),1.58 (d, J=6.82 Hz, 6H).

Example 66N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-morpholinyl)-4-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]morpholine(78 mg, 0.267 mmol) to give the desired product as an off-white solidafter evaporation and preciptation from EtOAc/MeOH. The final productwas collected as 0.110 g (58%). LCMS E-S (M+H) 502.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H), 8.95 (t, J=5.05 Hz, 1H), 8.40 (s, 1H),8.31 (d, J=5.30 Hz, 1H), 8.18 (s, 1H), 7.58 (s, 1H), 7.51 (dd, J=5.31,1.26 Hz, 1H), 5.90 (s, 1H), 5.39-5.30 (m, 1H), 4.42 (d, J=4.80 Hz, 2H),3.72-3.80 (m, 4H), 3.54-3.62 (m, 4H), 2.24 (s, 3H), 2.13 (s, 3H), 1.55(d, J=6.57 Hz, 6H).

Example 67N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 6-morpholinopyridine-3-boronic acid (55.6 mg 0.267mmol) to give the desired product as an off-white solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.110 g (82%). LCMS E-S (M+H) 502.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H), 9.06 (d, J=2.27 Hz, 1H), 8.88 (t, J=4.93Hz, 1H), 8.41 (dd, J=8.97, 2.40 Hz, 1H), 8.33 (s, 1H), 8.11 (s, 1H),7.00 (d, J=9.09 Hz, 1H), 5.91 (s, 1H), 5.34-5.28 (m, 1H), 4.40 (d,J=4.80 Hz, 2H), 3.71-3.78 (m, 4H), 3.55-3.62 (m, 4H), 2.23 (s, 3H), 2.13(s, 3H), 1.54 (d, J=6.82 Hz, 6H).

Example 68N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(methyloxy)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using [6-(methyloxy)-3-pyridinyl]boronic acid (40.9 mg 0.267mmol) to give the desired product as an off-white solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.060 g (50%). LCMS E-S (M+H) 447.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.58 (s, 1H), 9.07 (d, J=2.02 Hz, 1H), 8.90 (t, J=4.93Hz, 1H), 8.55 (dd, J=8.59, 2.53 Hz, 1H), 8.37 (s, 1H), 8.17 (s, 1H),7.01 (d, J=8.84 Hz, 1H), 5.91 (s, 1H), 5.36-5.28 (m, 1H), 4.41 (d,J=5.05 Hz, 2H), 3.95 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (d,J=6.57 Hz, 6H).

Example 696-[6-(Acetylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 2-acetamidopyridine-5-boronic acid pinacol ester (77mg, 0.294 mmol) to give the desired product as an off-white solid afterevaporation and preciptation from EtOAc/MeOH. The final product wascollected as 0.065 g (51%). LCMS E-S (M+H)=474.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (s, 1H), 10.76 (s, 1H), 9.19 (d, J=1.77 Hz, 1H),8.93 (t, J=4.80 Hz, 1H), 8.61 (dd, J=8.84, 2.27 Hz, 1H), 8.38 (s, 1H),8.25 (d, J=8.84 Hz, 1H), 8.20 (s, 1H), 5.91 (s, 1H), 5.30-5.40 (m, 1H),4.42 (d, J=5.05 Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 1.54(d, J=6.82 Hz, 6H).

Example 70N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 58 using 2-methylphenyl boronic acid (40.0 mg, 0.294 mmol) togive the desired product as an off-white solid after evaporation andpreciptation from MeOH. The final product was collected as 0.065 g(51%). LCMS E-S (M+H)=430.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.54 (s,1H) 8.89 (t, J=4.93 Hz, 1H) 8.39 (s, 1H) 7.74 (s, 1H) 7.56 (d, J=7.07Hz, 1H) 7.31-7.41 (m, 3H) 5.89 (s, 1H) 5.20-5.27 (m, 1H) 4.38 (d, J=4.80Hz, 2H) 2.40 (s, 3H) 2.21 (s, 3H) 2.12 (s, 3H) 1.53 (d, 6H).

Example 71N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 5-mL microwave vial were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (47.2 mg,0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol),and the mixture was degassed with nitrogen for 5 min. Next addedbis(triphenylphosphine) palladium(II) chloride (10.51 mg, 0.015 mmol)and the vial was sealed. The mixture was irradiated (microwave) at 140°C. for 12 h. The reaction mixture was filtered and the residue waswashed with DMSO. The DMSO solution of crude product was purified usingreverse-phase HPLC. The TFA salt of the product obtained was neutralizedwith saturated NaHCO₃, washed with water, and dried under high vacuum togive 12 mg (16%) of product. LCMS: (M+H)⁺=406.2 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.45-1.60 (m, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H),4.39 (d, J=4.6 Hz, 2H), 5.27 (quin, J=6.7 Hz, 1H), 5.90 (s, 1H), 7.91(s, 1H), 8.22-8.31 (m, 1H), 8.33 (m, 2H), 8.77 (t, J=4.7 Hz, 1H).

Example 726-(2-Amino-5-pyrimidinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 5-mL microwave vial was added DMSO (2 mL) and it was degassed withnitrogen for 5 min. Next added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinamine (49.7mg, 0.225 mmol), sodium carbonate (59.5 mg, 0.562 mmol) andbis(triphenylphosphine)palladium(II) chloride (9.20 mg, 0.013 mmol). Themixture was degassed for additional 5 min, sealed, and irradiated(microwave) at 135° C. for 15 h. The mixture was filtered and theresidue was washed with DMSO. The DMSO solution of the crude product waspurified using reverse-phase HPLC. The TFA salt of the product wasneutralized with saturated NaHCO₃ solution, filtered, washed with water,and dried under high vacuum to give 14 mg (17%) of product. LCMS E-S(M+H)=433.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.52 (d, J=6.4 Hz, 6H), 2.13(s, 3H), 2.22 (s, 3H), 4.40 (d, J=4.6 Hz, 2H) 5.22-5.41 (m, 1H), 5.90(s, 1H), 7.18 (m, 2H), 8.08 (s, 1H), 8.34 (s, 1H), 8.86 (m, 1H), 9.11(s, 2H), 11.58 (br. s., 1H).

Example 73N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 5-mL microwave vial were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol), 3-pyridinylboronic acid (29.9 mg, 0.243 mmol), DMSO(1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixturewas degassed with nitrogen for 10 min. Next was addedbis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol) andthe vial was sealed. The reaction mixture was irradiated (microwave) at140° C. overnight. The reaction mixture was filtered and the residue waswashed with DMSO. The crude product in DMSO was purified usingreverse-phase HPLC. The TFA salt of the product was neutralized usingsaturated NaHCO₃, filtered, washed with water and dried under highvacuum to give 33 mg (42%) of product. LCMS E-S (M+H)=417.2 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.56 (d, J=6.4 Hz, 6H), 2.13 (s, 3H), 2.23 (s, 3H),4.42 (d, J=4.29 Hz, 2H), 5.26-5.43 (m, 1H), 5.91 (s, 1H), 7.62 (dd,J=7.3, 5.0 Hz, 1H), 8.26 (s, 1H), 8.43 (s, 1H), 8.64 (d, J=7.8 Hz, 1H),8.70-8.79 (m, 1H), 8.96 (br. s., 1H), 9.46 (br. s., 1H), 11.59 (br. s.,1H).

Example 74N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(1H-indazol-5-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a 5-mL microwave vial were added6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg,0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol),and the mixture was degassed with nitrogen for 10 min. Next was addedbis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol).The contents were sealed and irradiated (microwave) at 140° C.overnight. The mixture was filtered and the residue was washed withDMSO. The crude product in DMSO was purified using reverse-phase HPLC.The TFA salt of the product was neutralized using saturated NaHCO₃,filtered, washed with water and dried under high vacuum to give 41 mg(48%) of product. LCMS E-S (M+H)=456.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.56 (d, J=6.8 Hz, 6H), 2.14 (s, 3H), 2.23 (s, 3H), 4.38-4.53 (m, 2H),5.27-5.49 (m, 1H), 5.91 (s, 1H), 7.59-7.75 (m, 1H), 8.24 (s, 2H), 8.37(s, 2H), 8.69 (s, 1H), 8.95-9.09 (m, 1H), 11.49-11.67 (m, 1H),13.21-13.35 (m, 1H).

Example 75N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(1H-indazol-6-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 from6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg,0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), andbis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol).The final product was collected as 55 mg (65%). LCMS E-S (M+H)=456.0 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.65 (m, J=6.4 Hz, 6H), 2.14 (s, 3H),2.23 (s, 3H), 4.43 (d, J=4.6 Hz, 2H), 5.36 (quin, J=6.7 Hz, 1H),5.87-5.97 (m, 1H), 7.52-7.72 (m, 2H) 7.92 (d, J=8.6 Hz, 1H), 8.08 (d,J=8.6 Hz, 1H), 8.16 (s, 1H), 8.26 (s, 1H), 8.37-8.49 (m, 2H), 8.96-9.14(m, 1H), 11.59 (br. s., 1H).

Example 766-(1H-1,2,3-Benzotriazol-5-yl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol), 1H-1,2,3-benzotriazol-5-ylboronic acid (39.7 mg,0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562 mmol) andbis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol).The final product was collected as 22 mg (26%). LCMS E-S (M+H)=457.1 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.57 (d, 6 J=6.4 Hz, H), 2.14 (s, 3H), 2.24(s, 3H), 4.43 (d, J=4.3 Hz, 2H), 5.31-5.46 (m, 1H), 5.91 (s, 1H), 8.07(br. s., 1H), 8.34 (s, 1H), 8.41 (m, 2H), 8.85 (br. s., 1H), 9.02 (br.s., 1H), 11.59 (br. s., 1H).

Example 77N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one(61.0 mg, 0.235 mmol), DMSO (1.5 mL) sodium carbonate (0.281 mL, 0.562mmol), and bis(triphenylphosphine)palladium(II) chloride (10.13 mg,0.014 mmol). The final product was collected as 19 mg (21%). LCMS E-S(M+H)=486.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50 (d, J=6.8 Hz, 6H), 2.12(s, 3H), 2.24 (s, 3H), 2.43 (s, 3H), 4.39 (d, J=4.6 Hz, 2H), 5.15-5.35(m, 1H), 5.89 (s, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.61 (s, 1H), 7.77-7.93(m, 2H), 8.70-8.85 (m, 1H), 10.79 (br. s., 1H), 10.87 (br. s., 1H),11.54 (br. s., 1H).

Example 78N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-indol-6-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one(63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg,0.015 mmol). The final product was collected as 10 mg (11%). LCMS E-S(M+H)=471.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (d, J=6.8 Hz, 6H), 2.13(s, 3H), 2.22 (s, 3H), 3.58 (s, 2H), 4.41 (d, J=4.8 Hz, 2H), 5.31 (quin,J=6.6 Hz, 1H), 5.91 (s, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.73 (d, J=1.0 Hz,1H), 7.87 (dd, J=7.8, 1.5 Hz, 1H), 8.12 (s, 1H), 8.37 (s, 1H), 9.00 (t,J=4.8 Hz, 1H), 10.55 (s, 1H), 11.58 (s, 1H).

Example 79N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one(63.1 mg, 0.243 mmol), DMSO (1.5 mL), sodium carbonate (0.281 mL, 0.562mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg,0.015 mmol). The final product was collected as 30 mg (34%). LCMS E-S(M+H)=471.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (d, J=6.4 Hz, 6H), 2.13(s, 3H), 2.22 (s, 3H), 3.40 (br. s., 2H), 4.41 (d, J=4.6 Hz, 2H),5.25-5.41 (m, 1H), 5.91 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 8.08-8.21 (m,3H), 8.34 (s, 1H), 8.96 (br. s., 1H), 10.64 (s, 1H), 11.58 (br. s., 1H).

Example 80N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one(63.3 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg,0.015 mmol). The final product was collected as 35 mg (40%). LCMS E-S(M+H)=472.4 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (d, J=6.4 Hz, 6H), 2.13(s, 3H), 2.22 (s, 3H), 4.41 (d, J=4.8 Hz, 2H), 5.30 (quin, J=6.6 Hz,1H), 5.91 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.92 (dd,J=8.3, 1.8 Hz, 1H), 8.10 (s, 1H), 8.30-8.41 (m, 1H), 8.98 (t, J=4.8 Hz,1H), 10.82 (s, 1H), 10.89 (s, 1H). 11.58 (s, 1H).

Example 81N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine(73.8 mg, 0.243 mmol), DMSO (2 mL), sodium carbonate (0.281 mL, 0.562mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg,0.015 mmol). The final product was collected as 12 mg (13%). LCMS E-S(M+H)=515.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (d, J=6.4 Hz, 6H), 2.13(s, 3H), 2.23 (m, 6H), 2.37-2.46 (m, 4H), 3.56-3.69 (m, 4H), 4.40 (d,J=4.6 Hz, 2H), 5.30 (quin, J=6.7 Hz, 1H), 5.91 (s, 1H), 6.99 (d, J=9.1Hz, 1H), 8.10 (s, 1H), 8.32 (s, 1H), 8.38 (dd, J=9.1, 2.5 Hz, 1H), 8.91(br. s., 1H), 9.03 (d, J=2.3 Hz, 1H).

Example 82N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol),1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine(73.6 mg, 0.243 mmol), 1,2-Dimethoxyethane (DME) (3 mL), water (1 mL)sodium carbonate (0.281 mL, 0.562 mmol), andbis(triphenylphosphine)palladium(II) chloride (12.23 mg, 0.015 mmol),wherein the reaction time was 30 min. The crude product was purified bycolumn chromatography (eluent: gradient of 0 to 15% (9:1MeOH/NH₄OH)/DCM). The product was dried under high vacuum and collectedas 58 mg (59%). LCMS E-S (M+H)=514.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.51-1.58 (m, 6H), 2.13 (s, 3H), 2.23 (s, 6H), 2.24 (s, 3H), 2.47 (m,4H), 3.24-3.30 (m, 4H), 4.41 (d, J=5.05 Hz, 2H), 5.30 (quin, J=6.63 Hz,1H), 5.90 (s, 1H), 7.07 (d, J=9.09 Hz, 2H), 8.06 (s, 1H), 8.15 (d,J=8.84 Hz, 2H), 8.30 (s, 1H), 8.92 (t, J=4.80 Hz, 1H), 11.55 (s, 1H).

Example 83N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.180 mmol), [6-(4-morpholinyl)-3-pyridinyl]boronic acid (48.8mg, 0.235 mmol), DMSO (2.0 mL), sodium carbonate (0.271 mL, 0.541 mmol),and bis(triphenylphosphine)palladium(II) chloride (10.13 mg, 0.014mmol), wherein the reaction time was 8 h. The mixture was filtered andthe residue was washed with DMSO. The crude product in DMSO was purifiedby reverse-phase HPLC (mobile phase: 25-60% CAN in H₂O, 0.1% TFA). TheTFA product salt obtained was neutralized with saturated NaHCO₃,filtered, washed with water, and dried under high vacuum to give theproduct as 24 mg (25%). LCMS E-S (M+H)=516.2 ¹H NMR (400 MHz, DMSO-d₆) δppm 1.50 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.42 (s, 3H),3.54-3.63 (m, 4H), 3.73 (m, 4H), 4.39 (d, J=4.80 Hz, 2H), 5.14-5.29 (m,1H), 5.89 (s, 1H), 6.97 (d, J=8.84 Hz, 1H), 7.63 (s, 1H), 8.37 (dd,J=9.09, 2.53 Hz, 1H), 8.68 (t, J=4.93 Hz, 1H), 8.98 (d, J=2.27 Hz, 1H),11.51 (s, 1H).

Example 84N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(50 mg, 0.134 mmol), 4-pyridinamine (12.59 mg, 0.134 mmol), cesiumcarbonate (131 mg, 0.401 mmol), 1,4-dioxane (2 mL), palladium(II)acetate (1.501 mg, 6.69 μmol) and BINAP (8.33 mg, 0.013 mmol), whereinthe reaction time was 2 h. The final product was collected as 29 mg(50%). LCMS E-S (M+H)=432.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45-1.59(d, J=6.8 Hz, 6H), 2.14 (s, 3H), 2.23 (s, 3H), 4.36 (d, J=5.0 Hz, 2H),5.16 (m, 1H), 5.91 (s, 1H), 7.09 (s, 1H), 7.99 (d, J=6.1 Hz, 2H), 8.12(s, 1H) 8.49 (d, J=6.6 Hz, 2H), 8.74 (t, J=5.1 Hz, 1H), 10.58 (s, 1H),11.58 (s, 1H).

Example 85N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.187 mmol), 5-amino-1,3-dihydro-2H-benzimidazol-2-one (33.5 mg,0.225 mmol), cesium carbonate (92 mg, 0.281 mmol), N,N-dimethylacetamide(DMA) (2 mL), palladium(II) acetate (2.52 mg, 0.011 mmol) and Xantphos(10.83 mg, 0.019 mmol) wherein the reaction temperature was 150° C. andreaction time was 8 h. The final product was collected as 25 mg (27%).LCMS E-S (M+H)=487.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.61 (m, 6H),2.13 (s, 3H), 2.23 (s, 3H), 4.38 (d, J=5.0 Hz, 2H), 5.20 (quin, J=6.6Hz, 1H), 5.90 (s, 1H), 6.79-6.91 (m, 2H), 8.04 (d, J=8.3 Hz, 1H),8.26-8.33 (m, 2H), 8.84 (t, J=5.0 Hz, 1H), 11.50 (s, 1H).

Example 866-{[4-(Aminocarbonyl)phenyl]amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.180 mmol), 4-aminobenzamide (29.5 mg, 0.217 mmol), cesiumcarbonate (88 mg, 0.271 mmol), N,N-dimethylacetamide (DMA) (1.5 mL),palladium(II) acetate (2.431 mg, 10.83 μmol) and Xantphos (10.44 mg,0.018 mmol) wherein the reaction temperature was 150° C. and reactiontime was 1 h. The final product was collected as 12 mg (14%). LCMS E-S(M+H)=488.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (d, J=6.4 Hz, 6H), 2.13(s, 3H), 2.23 (s, 3H), 2.32 (s, 3H), 4.35 (d, J=4.8 Hz, 2H), 4.99 (quin,J=6.8 Hz, 1H), 5.89 (s, 1H), 6.65 (s, 1H), 7.15 (br. s., 1H), 7.75-7.82(m, 1H), 7.84-7.96 (m, 4H), 8.56 (t, J=4.9 Hz, 1H), 9.77 (s, 1H).

Example 871-(1,1-Dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.174 mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine(68.7 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate(0.261 mL, 0.523 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (11.38 mg, 0.014mmol), wherein the reaction time was 40 min. The crude product waspurified by column chromatography (eluent: gradient of 0 to 15% (9:1MeOH/NH₄OH)/DCM). The final product was collected as a solid, 41 mg(43%). LCMS E-S (M+H)=543.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (s,9H), 2.12 (s, 3H), 2.24 (m, 7H), 2.38 (s, 3H), 2.39-2.49 (m, 4H), 3.34(s, 3H), 4.38 (m, 2H), 5.88 (s, 1H), 6.98 (d, J=9.09 Hz, 1H), 7.59 (s,1H), 8.93-8.97 (m, 1H), 11.49-11.57 (m, 1H), 11.53 (s, 1H), 11.53 (s,1H).

Example 881-(1,1-Dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.174 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one(58.9 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate(0.261 mL, 0.523 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (11.38 mg, 0.014mmol) wherein the reaction time was 40 min. The crude product waspurified by column chromatography (eluent: gradient of 0 to 15% (9:1MeOH/NH₄OH)/DCM). The final product was collected as a solid, 24 mg(27%). LCMS E-S (M+H)=500.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.77 (m,9H), 2.12 (s, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 4.38 (d, J=4.55 Hz, 2H),5.89 (s, 1H), 7.06 (d, J=8.08 Hz, 1H), 7.59 (s, 1H), 7.72-7.86 (m, 2H),8.73 (br. s., 2H), 10.74-10.92 (m, 1H), 11.53 (br. s., 1H).

Example 891-(1,1-Dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.174 mmol), [6-(4-morpholinyl)-3-pyridinyl]boronic acid (47.1mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261mL, 0.523 mmol) and PdCl₂(dppf)-CH₂Cl₂ adduct (11.38 mg, 0.014 mmol)wherein the reaction time was 40 min. The crude product was purified bycolumn chromatography (eluent: gradient of 0 to 15% (9:1MeOH/NH₄OH)/DCM). The final product was collected as a solid, 61 mg(65%). LCMS E-S (M+H)=530.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (s,9H), 2.12 (s, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 3.52-3.64 (m, 4H),3.68-3.80 (m, 4H), 4.38 (d, J=5.05 Hz, 2H), 5.88 (s, 1H), 6.99 (d,J=9.09 Hz, 1H), 7.61 (s, 1H), 8.34 (dd, J=8.84, 2.53 Hz, 1H), 8.68 (t,J=5.05 Hz, 1H), 8.97 (d, J=2.27 Hz, 1H), 11.53 (s, 1H).

Example 906-(2,1,3-Benzoxadiazol-5-yl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.180 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole(57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg,0.018 mmol) wherein the reaction time was 8 h. The final product wascollected as 17 mg (20%). LCMS LCMS E-S (M+H)=472.4 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.53 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.27 (s, 3H) 4.42(d, J=4.8 Hz, 2H) 5.32 (quin, J=6.6 Hz, 1H), 5.90 (s, 1H), 8.00 (s, 1H),8.23 (d, J=9.4 Hz, 1H), 8.54-8.64 (m, 1H), 8.79 (t, J=4.7 Hz, 1H), 8.91(s, 1H), 11.54 (br. s., 1H).

Example 916-(2-Amino-6-quinazolinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 74 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(70 mg, 0.180 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole(57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg,0.018 mmol), wherein the reaction time was 8 h. The final product wascollected as 28 mg (31%). LCMS E-S (M+H)=497.3 ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.52 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.26 (s, 3H), 4.41 (d, J=5.0Hz, 2H) 5.30 (quin, J=6.6 Hz, 1H), 5.89 (s, 1H), 7.16 (br. s., 2H), 7.56(d, J=9.1 Hz, 1H), 7.78 (s, 1H) 8.60 (dd, J=8.8, 2.0 Hz, 1H), 8.69 (d,J=1.8 Hz, 1H), 8.76 (t, J=4.9 Hz, 1H), 9.28 (s, 1H), 11.53 (s, 1H).

Example 92N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-{4-[(methylamino)sulfonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (66.5mg, 0.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (8.4mg, 0.01 mmol) were suspended in DME/water (4 mL, 3:1) and stirred for10 min under nitrogen at room temperature. Sodium bicarbonate (52 mg,0.62 mmol) was added and the heterogenous mixture was irradiated(microwave) at 150° C. for 30 min. After cooling to room temperature,water was added to the black mixture, and the contents were vacuumfiltered. The crude product was dissolved in DCM/MeOH (1:1) andpreabsorbed onto silica gel. The product was purified by silica gelchromatography (eluent: DCM/MeOH/NH₄OH, gradient of 0 to 90:10:1). Thelight beige solid that was collected was suspended in EtOH, sonicated,and filtered. The solid was then air-dried for 15 min, and then invacuum oven overnight. The final product was collected as 77 mg (70%).LCMS E-S (M+H)=523.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.54 (br. s., 1H)8.78 (t, J=5.05 Hz, 1H) 8.43 (m, J=8.59 Hz, 2H) 7.93 (m, J=8.59 Hz, 2H)7.78 (s, 1H) 7.58 (br. s., 1H) 5.89 (s, 1H) 5.29 (quin, J=6.63 Hz, 1H)4.40 (d, J=4.80 Hz, 2H) 2.46 (d, J=1.26 Hz, 6H) 2.25 (s, 3H) 2.12 (s,3H) 1.52 (s, 3H) 1.51 (s, 3H).

Example 936-[4-(Acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 93 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol), [4-(acetylamino)phenyl]boronic acid (55.4 mg, 0.31mmol), bis(triphenylphosphine)palladium(II) chloride (8.4 mg, 0.01mmol), DME/water (4 mL, 3:1) and sodium bicarbonate (52 mg, 0.62 mmol).The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed ontosilica gel. The product was purified by silica gel chromatography(eluent: DCM/MeOH/NH₄OH. gradient of 0 to 80:20:2). The collected solidwas suspended in EtOH/EtOAc (1:1), sonicated, and filtered. Afterfurther washing with hexanes, the solid was then air-dried for 15 min,and then in vacuum oven overnight. The final product was collected as 70mg (69%). LCMS E-S (M+H)=487.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.53(br. s., 1H) 10.16 (s, 1H) 8.73 (t, J=5.05 Hz, 1H) 8.17 (m, J=8.84 Hz,2H) 7.74 (m, J=8.84 Hz, 2H) 7.64 (s, 1H) 5.89 (s, 1H) 5.25 (quin, J=6.69Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 2.43 (s, 3H) 2.25 (s, 3H) 2.12 (s, 3H)2.09 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H).

Example 946-[4-(Aminocarbonyl)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 93 using6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol), [4-(aminocarbonyl)phenyl]boronic acid (52.9 mg, 0.31mmol), bis(triphenylphosphine)palladium(II) chloride (8.7 mg, 0.01mmol), DME/water (4 mL, 3:1) and sodium bicarbonate (54 mg, 0.62 mmol).The crude product was dissolved in DCM/MeOH (1:1) and preabsorbed ontosilica gel. The product was purified by silica gel chromatography(eluent: DCM/MeOH/NH₄OH (gradient 0 to 90:10:1). The collected solid wassuspended in EtOH, sonicated, and filtered. After further washing withEtOH/DCM, the filtered solid was then air-dried for 15 min, and then invacuum oven overnight. The final product was collected as 70 mg (69%).LCMS E-S (M+H)=459.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.58 (s, 1H) 9.00(t, J=4.93 Hz, 1H) 8.41 (s, 1H) 8.36 (s, 1H) 8.34 (s, 1H) 8.24 (s, 1H)8.13 (s, 1H) 8.06 (s, 1H) 8.04 (s, 1H) 7.51 (s, 1H) 5.91 (s, 1H) 5.37(quin, J=6.69 Hz, 1H) 4.42 (d, J=4.80 Hz, 2H) 2.23 (s, 3H) 2.13 (s, 3H)1.56 (s, 3H) 1.55 (s, 3H).

Example 95N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{[2-(2-pyridinylamino)ethyl]amino}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(80 mg, 0.21 mmol) and (2-aminoethyl)-2-pyridinylamine (88 mg, 0.64mmol) were suspended in 2 mL of NMP and irradiated (microwave) asfollows: 180° C. for 30 min, 200° C. for 30 min, 220° C. for 30 min,230° C. for 30 min and then 240° C. for 1 h. After cooling to roomtemperature, some of the solvent was removed in vacuo and the residuewas purified by silica gel chromatography (eluent: DCM/MeOH/NH₄OH,gradient 0 to 90:10:1). The collected solid was partitioned betweenwater and EtOAc/toluene (1:1) and then extracted twice withDCM/isopropanol. The combined organic layers were washed with water,dried over MgSO₄, filtered, and concentrated in vacuo to afford a darkbrown oil. After drying under vacuum overnight, the residue was againpurified by silica gel chromatography (eluent: DCM/MeOH/NH₄OH (gradient0 to 90:10:1). The collected solid was suspended in EtOH, sonicated, andfiltered. The solid was further washed with EtOH/DCM, filtered, anddried in vacuum-oven for 2 days. The final product was collected as 47mg (45%). LCMS E-S (M+H)=475.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.56(br. s., 1H) 8.47 (t, J=5.05 Hz, 1H) 7.97 (dd, J=4.93, 1.14 Hz, 1H) 7.85(s, 1H) 7.32-7.39 (m, 2H) 6.65 (s, 1H) 6.61 (t, J=5.43 Hz, 1H) 6.46-6.51(m, 2H) 5.89 (s, 1H) 4.97 (quin, J=6.69 Hz, 1H) 4.32 (d, J=5.05 Hz, 2H)3.49 (dt, J=15.28, 5.62 Hz, 4H) 2.21 (s, 3H) 2.13 (s, 3H) 1.44 (s, 3H)1.43 (s, 3H).

Example 96N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one (200 mg, 0.881 mmol) (J.Med. Chem. 2003; 46; 9; 1627-1635), bis(pinacolato)diboron (268 mg,1.057 mmol), Pd(dppf) (35.7 mg, 0.044 mmol) and potassium acetate (259mg, 2.64 mmol) were suspended in 1,4-Dioxane (8 mL), and stirred withheating at 100° C. for 1 h. After cooling to room temperature,6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(329 mg, 0.881 mmol), bis(triphenylphosphine)palladium(II) chloride(71.9 mg, 0.088 mmol) and sodium bicarbonate (222 mg, 2.64 mmol) wereadded, followed by DME (5 mL) and water (3 mL). The reaction mixture wasirradiated (microwave) at 120° C. for 2 h. The reaction mixture wascooled cooled to room temperature and filtered through Na₂SO₄. Thecontents were purified directly by silica gel chromatography (eluent: 5%MeOH/CH₂Cl₂) to furnish the desired product as a grey solid afterevaporation and precipitation from warm EtOAc/MeOH (1:9). The productwas collected as 55 mg (13%). LCMS E-S (M+H)=486.3 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.57 (br. s., 1H), 10.74 (s, 1H), 8.99 (d, J=2.27 Hz,1H), 8.93 (t, J=4.93 Hz, 1H), 8.44 (d, J=1.77 Hz, 1H), 8.37 (s, 1H),8.16 (s, 1H), 5.91 (s, 1H), 5.29-5.40 (m, 1H), 4.42 (d, J=5.05 Hz, 2H),3.04 (t, J=7.58 Hz, 2H), 2.53-2.62 (m, 2H), 2.23 (s, 3H), 2.13 (s, 3H),1.54 (d, 6H).

Example 97N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{6-[(methylamino)sulfonyl]-3-pyridinyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

5-Bromo-N-methyl-2-pyridinesulfonamide (225 mg, 0.896 mmol),Bis(pinacolato)diboron (296 mg, 1.165 mmol), Pd(dppf) (35.7 mg, 0.044mmol) and potassium acetate (264 mg, 2.69 mmol) were suspended in1,4-Dioxane (8 mL), and stirred with heating at 100° C. for 1 h. Aftercooling to room temperature,6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(368 mg, 0.986 mmol), bis(triphenylphosphine)palladium(II) chloride(73.2 mg, 0.090 mmol) and sodium bicarbonate (226 mg, 2.69 mmol) wereadded, followed by DME (5 mL) and water (3 mL). The reaction mixture wasirradiated (microwave) at 120° C. for 2 h. The reaction mixture wascooled cooled to room temperature and filtered through Na₂SO₄. Thecontents were purified directly by silica gel chromatography (eluent:15% MeOH/CH₂Cl₂) to furnish the desired product as a grey solid afterevaporation and precipitation from warm EtOAc/MeOH (1:9). The productwas again purified by silica gel chromatography (eluent: 5% MeOH/CH₂Cl₂)to afford the final product as a white solid, 83 mg (18%). LCMS E-S(M+H)=510.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.59 (br. s., 1H), 9.56 (d,J=1.52 Hz, 1H), 8.96 (s, 1H), 8.86 (dd, J=8.34, 2.27 Hz, 1H), 8.46 (s,1H), 8.34 (s, 1H), 8.12 (d, J=8.34 Hz, 1H), 7.85 (br. s., 1H), 5.91 (s,1H), 5.27-5.46 (m, 1H), 4.43 (d, J=4.80 Hz, 2H), 2.60 (s, 3H), 2.23 (s,3H), 2.13 (s, 3H), 1.56 (d, 6H).

Intermediate 17 5-Bromo-N-methyl-2-pyridinesulfonamide

5-Bromo-2-pyridinesulfonyl chloride (500 mg, 1.949 mmol) was added to a0° C. solution of pyridine (0.315 ml, 3.90 mmol), methylamine (0.975 ml,1.949 mmol, 2M in THF) and CH₂Cl₂ (2 mL). The reaction mixture wasstirred at room temperature for 1 hr, then quenched with brine. Thecontents were extracted with DCM, dried, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography(eluent: 50%, EtOAC/CH₂Cl₂). The product was collected as a clear oil,225 mg (75%). LCMS E-S (M+H)=251.1. ¹H NMR (400 MHz, Chloroform-d) δ ppm8.77 (s, 1H), 8.07 (dd, J=8.34, 2.27 Hz, 1H), 7.92 (d, J=8.34 Hz, 1H),5.45 (d, J=5.05 Hz, 1H), 2.76 (d, 3H).

Intermediate 18 1-{[4-(Methyloxy)phenyl]methyl}-1H-pyrazol-5-amine

Hydrazine hydrate (12.82 g, 400 mmol) was added dropwise to a cooled(<20° C.) solution of 2-propenenitrile (21.76 g, 410 mmol) and ethanol(200 mL). After 16 h stirring the reaction mixture was cooled in an icewater bath and 4-(methyloxy)benzaldehyde (53.8 g, 395 mmol) was addeddropwise. The mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated to dryness. The residue was dissolvedin n-butanol (200 mL), sodium hydroxide was added (1 g, 25.00 mmol), andthe mixture heated at 120° C. for 6 h. The reaction mixture wasconcentrated to 50% volume under reduced pressure, poured onto 300 mL ofwater, and then extracted with Et₂O (2×200 mL). The combined etherphases were extracted with 1N HCl (3×100 mL). The combined HCl extractswere combined and cooled in an ice/water bath. Added next was 6N NaOHuntil basic (pH>12). The contents were extracted with Et₂O (4×100 mL),washed with water, dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified via silica gel chromatography(eluent: 0-50% EtOAc:Hex). The final product was collected as 8.94 g(11%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.79 (s, 3H), 5.14 (s, 2H),5.55 (d, J=1.77 Hz, 1H), 6.81-6.94 (m, 2H), 7.12 (d, J=8.84 Hz, 2H),7.31 (d, J=2.02 Hz, 1H).

Intermediate 19 1-Cyclobutyl-3-methyl-1H-pyrazol-5-amine

(2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) andcyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL)and heated at 75° C. for 16 h. After cooling to room temperature, thesolvent was removed under reduced pressure. The crude residue wassuspended in saturated NaHCO₃ (30 mL) and EtOAc (50 mL), and stirred for10 min. The phases were separated and the aq. phase extracted with EtOAc(3×50 mL). The combined EtOAc extracts were washed with brine, driedover MgSO₄, filtered, and concentrated in vacuo. The crude residue waspurified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, thengradient to 100% EtOAc). The final product was collected as 0.4 g (16%).LCMS E-S (M+H)═:152.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00(m, 2H) 2.21 (s, 3H) 2.32-2.43 (m, 2H) 2.69 (ddd, J=10.55, 9.41, 2.53Hz, 2H) 3.26-3.55 (br s, 2H) 4.48-4.59 (m, 1H) 5.36 (s, 1H)

Intermediate 20 1-Cyclopentyl-3-methyl-1H-pyrazol-5-amine

The title compound was prepared in the same manner as described forintermediate 19 using cyclopentylhydrazine hydrochloride (2 g, 14.64mmol), (2Z)-3-amino-2-butenenitrile (1.202 g, 14.64 mmol) and ethanol(20 mL). The final product was collected as 0.57 g (24%). LCMS E-S(M+H)=166.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.69 (m, 2H),1.86-1.95 (m, 2H), 1.99-2.09 (m, 4H), 2.19 (s, 3H), 3.46 (br. s., 2H),4.38 (quin, J=7.89 Hz, 1H), 5.36 (s, 1H).

Intermediate 21 1-(Phenylmethyl)-1H-pyrazol-5-amine

A solution of hydrazine hydrate (14.55 mL, 300 mmol) and ethanol (75 mL)was cooled in an ice water bath and then 2-propenenitrile (15.3 g, 288mmol) was added dropwise. After stirring at room temperature for 2 h,benzaldehyde (31.8 g, 300 mmol) was added dropwise and the reactionmixture was allowed to stir at room temperature for 2 d. The solvent wasremoved under reduced pressure. The crude oil was cooled in an ice/waterbath followed by dropwise addition of a n-BuONa solution (Na 6.9 g, (300mmol) in n-Butanol (300 mL)). The reaction mixture was heated at refluxfor 1 h, and then cooled to room temperature. The contents were pouredonto 300 mL of water and then extracted with Et₂O (2×200 mL). The etherphase was extracted with 1N HCl (3×100 mL). The combined HCl extractswere combined and cooled in a ice/water bath, followed by addition of 6NNaOH until basic (pH>12). The mixture was extracted with Et₂O (4×100mL), washed with water, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The crude residue was purified via silica gelchromatography (eluent: 0 to 50% EtOAc:Hex). The final product wascollected as 6.96 g (14%). LCMS E-S (M+H)=174.0. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 3.39 (br. s., 2H), 5.23 (s, 2H), 5.59 (d, J=1.77 Hz,1H), 7.17 (d, J=6.82 Hz, 2H), 7.28-7.37 (m, 4H)

Intermediate 22 1,1-Dimethylethyl2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate

Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol(100 mL) and stirred at room temperature for 3 h. The solvent wasremoved in vacuo, and the crude residue was suspended in acetic acid(140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) inportions over 3 minutes. The contents were stirred at room temperaturefor 60 h. The solvent was removed in vacuo, and the crude residue wassuspended in DCM (100 mL). The reaction mixture was adjusted to pH 7with 6N NaOH. The layers were separated, and the aq. layer extractedwith DCM. The combined organic layers were washed with saturated NaHCO₃,and brine. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo to afford the product as a solid, 18.4 g (88%). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m,1H), 1.59-1.69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d,J=11.62 Hz, 2H), 4.36 (br. s., 1H), 8.07-8.34 (m, 1H).

Intermediate 23 Tetrahydro-2H-pyran-4-ylhydrazine

1,1-Dimethylethyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate wasadded to 1,4-Dioxane (10 mL) followed by hydrochloric acid (4M in1,4-Dioxane, 10 mL, 329 mmol). The reaction mixture was stirred at roomtemperature for 60 h. The reaction mixture was filtered to afford theproduct as a solid, 1.02 g. (72%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.45 (qd, J=11.79, 4.29 Hz, 2H), 1.81-2.01 (m, 2H), 3.00-3.19 (m, 1H),3.20-3.35 (m, 2H), 3.78-3.97 (m, 2H), 6.5-9.5 (br m, 3H).

Intermediate 24 3-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine

(2Z)-3-Amino-2-butenenitrile (0.538 g, 6.55 mmol),tetrahydro-2H-pyran-4-ylhydrazine (1 g, 6.55 mmol) and triethylamine(0.913 mL, 6.55 mmol) were added to ethanol (300 mL), and the reactionmixture was stirred at 75° C. for 16 hours. The solvent was removed invacuo, and the crude material suspended in EtOAc. The organic phase waswashed with water and then brine. The organic layer was then dried overMgSO₄, filtered, and concentrated in vacuo. Half of the crude materialwas purified by reverse HPLC (mobile phase: 0-30% ACN/H₂O, 0.1% TFA) toafford 380 mg of the desired product. The other half of the crudematerial was purified via silica gel chromatography (eluent: 0% to 100%EtOAc:Hex then 0% to 20% MeOH:DCM). An additional 300 mg of the desiredproduct was obtained (overall yield: 57%). LCMS E-S (M+H)=182.0. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.78 (dd, 2H), 1.94 (qd, J=12.13, 4.55 Hz,2H), 2.19 (s, 3H), 3.30-3.46 (m, 2H), 3.99 (dd, J=11.49, 4.17 Hz, 2H),4.49 (m, J=11.65, 11.65, 4.11, 3.92 Hz, 1H), 5.53 (s, 1H).

Intermediate 25 6-Methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol

A mixture of 1-(phenylmethyl)-1H-pyrazol-4-amine (6.25 g, 36.1 mmol),ethyl 3-oxobutanoate (4.70 g, 36.1 mmol), acetic acid (0.2 mL, 3.49mmol) and benzene (50 mL) were refluxed for 16 h (Dean-Stark trap used).The solvent was removed under reduced pressure and the crude residuepurified via silica gel chromatography (eluent; 0 to 60% EtOAc:Hex). Thecollected product (7.35 g, 25.8 mmol) was then dissolved in 10 mL ofDowtherm A and this solution added dropwise to 10 mL of refluxingDowtherm A. After refluxing for an additional 20 minutes, the reactionmixture was cooled to room temperature, and 20 mL of petroleum etherwere added. After stirring at room temperature for 16 hr, the solidproduct was filtered and dried on hi-vacuum. The final product wascollected as 6.23 g (72%). LCMS E-S (M+H)=240.0. ¹H NMR (400 MHz, MeOD)ppm 4.89 (s, 3H), 5.59 (s, 2H), 6.17 (br. s., 1H), 7.17 (d, J=6.82 Hz,2H), 7.25-7.37 (m, 3H), 8.05 (s, 1H).

Intermediate 264-Bromo-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine

Phosphorus oxybromide (5.31 g, 18.54 mmol) was added to a suspension of6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (3.08 g, 12.87mmol) and toluene (25 mL). The contents were heated to reflux for 1 h,wherein 10 mL DMF were added during this process. The solvent wasremoved under reduced pressure. The crude residue was suspended in 30 mLwater containing ice. The contents were adjusted to pH=10 by addition ofsat. NaHCO₃. The solid product was filtered and dried under hi-vacuum.The final product was collected as 3.55 g (91%). LCMS E-S(M+H)=302.1/304.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.61 (s, 3H), 5.65(s, 2H), 7.16-7.35 (m, 5H), 7.48 (s, 1H), 8.12 s, 1H).

Intermediate 276-Methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carbonitrile

A mixture of4-bromo-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine (3.45 g,11.42 mmol), dicyanozinc (1.542 g, 13.13 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.523 g, 0.571 mmol), SPhos(0.562 g, 1.370 mmol), DMF (49 mL), and water (0.5 mL) was degassed withnitrogen for 10 minutes. The reaction mixture was heated at 120° C. for2 hours, and then cooled to room temperature. The contents wereconcentrated to 50% volume and then 50 mL of 1N NaOH and 50 mL of EtOAcwere added. The solids were filtered off. The phases were separated andthe aqueous phase extracted with EtOAc (3×50 mL). The combined EtOAcextracts were washed with water (3×50 mL), brine (50 mL), dried overMgSO₄, filtered, and concentrated in vacuo. The crude product containingSPhos reagent (˜30-40%) was collected as 3.69 g and used without furtherpurification. LCMS E-S (M+H)=249.1. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm2.77 (s, 3H), 5.73 (s, 2H), 7.08-7.44 (m, 6H), 8.16 (s, 1H)

Intermediate 286-Methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

6-Methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carbonitrile (1g), sodium hydroxide (0.805 g, 20.14 mmol), ethanol (25 mL) and water(10 mL) were heated at reflux for 2 hours. After cooling to roomtemperature, the solvent was removed under reduced pressure. The crudeproduct was suspended in water (50 mL) and acidified by dropwiseaddition of 6N HCl. The solid product was filtered off and dissolved in100 ml of EtOAc. The solution dried over MgSO₄, filtered, andconcentrated in vacuo. The final product was obtained as 0.730 g. LCMSE-S (M+H)=267.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.71 (s, 3H), 5.70 (s,2H), 7.15-7.37 (m, 5H), 7.63 (s, 1H), 8.33 (s, 1H), 13.86 (s, 1H).

Intermediate 29 ethyl 4-cyclopropyl-2,4-dioxobutanoate

Sodium metal (2.411 g, 105 mmol) was dissolved in ethanol (50 mL). Thesolution was heated to reflux followed by addition of a mixture of1-cyclopropylethanone (8.4 g, 100 mmol) and diethyl oxalate (14.59 g,100 mmol) dropwise over 30 minutes. The reaction mixture was heated atreflux for an additional 2 h, and then allowed to cool to roomtemperature over a 2 d period. The contents were diluted with water (200mL) and acidified by dropwise addition of 6N HCl. The contents wereextracted with EtOAc (3×75 mL), washed with water, brine, dried overMgSO₄, filtered, and concentrated in vacuo. The final product wascollected as 14.3 g (74%). LCMS E-S (M+H)=184.8 ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.03 (d, J=7.83 Hz, 2H) 1.13-1.19 (m, 2H) 1.31 (t,J=7.07 Hz, 3H) 1.81-1.90 (m, 1H) 4.29 (q, J=7.16 Hz, 2H) 6.43 (s, 1H).

Intermediate 30 Ethyl6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g,14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol)and benzene (50 mL) were heated at 63° C. for 16 h. The solvent wasremoved under reduced pressure. The crude residue was purified viasilica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 gof the desired cyclized product and 1.71 g of the uncyclized adduct. Theuncyclized adduct was dissolved in 25 mL of AcOH and heated to refluxfor 16 hours. The solvent was removed under reduced pressure and theresidue purified via silica gel chromatography (eluent: 0 to 25%EtOAc:Hex) to afford an additional 1.15 g of the desired cyclizedproduct (combined yield=71%). LCMS E-S (M+H)=352.3. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.07-1.13 (m, 4H) 1.38 (t, J=7.07 Hz, 3H) 2.39 (s, 1H)3.67 (s, 3H) 4.41 (q, J=7.07 Hz, 2H) 5.51 (s, 2H) 6.84 (d, J=8.84 Hz,2H) 7.21 (d, J=8.59 Hz, 2H) 7.64 (s, 1H) 8.23 (s, 1H).

Intermediate 31 Ethyl6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a 20 mL microwave vial were combined ethyl6-cyclopropyl-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(2.05 g, 5.83 mmol), trifluoroacetic acid (6.74 ml, 88 mmol) and anisole(1.912 ml, 17.50 mmol). The reaction vessel was sealed and irradiated(microwave) at 100° C. for 5 minutes. After cooling to room temperature,the reaction mixture was concentrated in vacuo. The residue was dilutedwith water (20 mL) and then saturated NaHCO₃ until basic. The contentswere extracted with DCM (4×20 mL). The combined organic layers werewashed with water, brine, dried over MgSO₄, filtered and concentrated invacuo. The crude product was purified via silica gel chromatography(eluent: 0 to 20% EtOAc:Hex). The final product was obtained as 1.06 g(79%). LCMS E-S (M+H)=232.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.21(m, 4H) 1.41 (t, J=7.07 Hz, 3H) 2.33-2.46 (m, 1H) 4.44 (q, J=7.07 Hz,2H) 7.67 (s, 1H) 8.26 (d, J=1.26 Hz, 1H) 13.75 (s, 1H).

Intermediate 32 Ethyl1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg,0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL),followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol).After 20 minutes stirring,0-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) wasadded and the mixture stirred at room temperature for 16 h. The contentswere diluted with EtOAc, and then washed with brine, and saturatedNaHCO₃. The organic phase was dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was purified via silica gelchromatography (eluent: 0 to 50% EtOAc). The final product as collectedas 106 mg (50%). LCMS E-S (M+H)=274.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.00-1.14 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.34-2.47 (m, 1H), 4.44 (q,J=7.07 Hz, 2H), 6.39 (s, 2H), 7.64 (s, 1H), 8.09 (s, 1H).

Intermediate 33 Ethyl6-cyclopropyl-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

A solution of ethyl 4-cyclopropyl-2,4-dioxobutanoate (700 mg, 3.76mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (523 mg, 3.76 mmol)and benzene (20 mL) were heated at 65° C. for 6 hr, and then allowed tocool to room temperature for 2 d. The solvent was removed under reducedpressure and the residue purified via silica gel chromatography (eluent:0 to 25% EtOAc:Hex). The final product was collected as 0.77 g (71%).LCMS E-S (M+H)=288.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.11 (m,2H), 1.13-1.20 (m, 4H), 1.47 (t, J=7.20 Hz, 6H), 1.55 (d, J=6.82 Hz,12H), 2.16-2.25 (m, 2H), 2.68 (s, 6H), 4.49 (q, J=7.07 Hz, 4H), 5.20(spt, J=6.78 Hz, 2H), 7.41 (s, 1H).

Intermediate 34 Ethyl1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 33 using 1-cyclobutyl-3-methyl-1H-pyrazol-5-amine (400 mg,2.65 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (487 mg, 2.65 mmol)and benzene (50 mL), wherein the reaction time was 4 h. The finalproduct was collected as 0.556 g (70%). LCMS E-S (M+H)=300.6 ¹H NMR (400MHz, CHLOROFORM-d) δ ppm 1.02-1.22 (m, 4H) 1.47 (t, J=7.07 Hz, 3H)1.80-2.01 (m, 2H) 2.15-2.28 (m, 1H) 2.38-2.51 (m, 2H) 2.70 (s, 3H) 2.82(td, J=9.85, 2.53 Hz, 2H) 4.49 (q, J=7.07 Hz, 2H) 5.32-5.57 (m, 1H) 7.41(s, 1H).

Intermediate 35 ethyl1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 33 using 1-cyclopentyl-3-methyl-1H-pyrazol-5-amine (570 mg,3.45 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (635 mg, 3.45 mmol),and benzene (50 mL) wherein the reaction time was 4 h. The crude productwas purified via silica gel chromatography (eluent: 0 to 10% EtOAc:Hex).The final product was collected as 0.740 g (68%). LCMS E-S (M+H)=314.3¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04-1.21 (m, 4H) 1.47 (t, J=7.20Hz, 3H) 1.73 (br. s., 2H) 2.00 (d, J=2.78 Hz, 2H) 2.08-2.16 (m, 4H) 2.21(s, 1H) 2.67 (s, 3H) 4.49 (q, J=7.16 Hz, 2H) 5.32 (t, J=7.83 Hz, 1H)7.40 (s, 1H).

Intermediate 36 ethyl6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 33 using ethyl 4-cyclopropyl-2,4-dioxobutanoate (481 mg,2.61 mmol), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (400 mg,2.61 mmol), and toluene (20 mL), wherein the reaction time was 3 h. Thecrude product was purified via silica gel chromatography (eluent: 0 to10% EtOAc:Hex). The final product was collected as 0.24 g (30%). LCMSE-S (M+H)=302.5. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02-1.23 (m, 4H)1.47 (t, J=7.20 Hz, 3H) 1.79 (s, 9H) 2.19 (s, 1H) 2.66 (s, 3H) 4.49 (q,J=7.07 Hz, 2H) 7.44 (s, 1H).

Intermediate 37 Ethyl6-cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

1-(1-Cyclopropylethyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 3.03 mmol)and ethyl 4-cyclopropyl-2,4-dioxobutanoate (557 mg, 3.03 mmol) weresuspended in Toluene (10 mL) and heated at 70° C. for 16 h. The solventwas removed in vacuo and the crude residue was purified via silica gelchromatography (eluent: gradient of 0 to 10% EtOAc:Hex). The finalproduct was collected as a solid, 0.722 g (76%). LCMS E-S (M+H)=314.3 ¹HNMR (400 MHz, DMSO-d₆) ppm 0.17-0.32 (m, 2H), 0.39 (m, J=9.69, 4.82,4.82, 4.67 Hz, 1H), 0.51-0.62 (m, 1H), 0.94-1.11 (m, 4H), 1.28-1.41 (m,4H), 1.58 (d, J=6.82 Hz, 3H), 2.30-2.38 (m, 1H), 2.56 (s, 3H), 4.19 (dq,J=9.44, 6.87 Hz, 1H), 4.43 (q, J=7.07 Hz, 2H), 7.48 (s, 1H)

Intermediate 38 Ethyl1-cyclohexyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79mmol). The final product was collected as a solid, 0.827 g (91%). LCMSE-S (M+H)=328.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.10 (m, 3H),1.20-1.30 (m, 1H), 1.37 (t, J=7.07 Hz, 3H), 1.41-1.52 (m, 2H), 1.70 (d,1H), 1.79-1.98 (m, 6H), 2.30-2.38 (m, 1H), 2.54 (s, 3H), 4.42 (q, J=7.07Hz, 2H), 4.60-4.74 (m, 1H), 7.44 (s, 1H).

Intermediate 39 Ethyl6-cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

3-Methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazol-5-amine (500 mg, 2.57mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (474 mg, 2.57 mmol)were suspended in Toluene (10 mL) and heated at 70° C. for 5 h. Thesolvent was removed in vacuo and the crude residue was purified viasilica gel chromatography (eluent: gradient of 0 to 10% MeOH:DCM). Thefinal product was collected as a solid, 0.722 g (76%). LCMS E-S(M+H)=343.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03-1.11 (m, 4H), 1.38 (t,J=7.07 Hz, 3H), 1.83 (d, J=6.06 Hz, 2H), 2.12-2.22 (m, 4H), 2.27 (s,3H), 2.35 (m, J=7.83, 7.83, 5.05, 4.80 Hz, 1H), 2.54 (s, 3H), 2.94 (d,J=6.57 Hz, 2H), 4.42 (q, J=7.16 Hz, 2H), 4.57-4.73 (m, 1H), 7.46 (s,1H).

Intermediate 40 Ethyl6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

A mixture of 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine(380 mg, 2.097 mmol), ethyl(3Z)-4-cyclopropyl-4-hydroxy-2-oxo-3-butenoate (386 mg, 2.097 mmol) andacetic acid (50 mL) were heated at 117° C. for 2 hours. The solvent wasremoved in vacuo, and the crude residue was purified via silica gelchromatography (eluent: 0 to 25% EtOAc:Hex). The desired product wascollected as a solid, 300 mg (43%). LCMS E-S (M+H)=330.3 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.00-1.12 (m, 4H), 1.37 (t, J=7.20 Hz, 3H), 1.82(dd, J=12.51, 2.40 Hz, 2H), 2.16 (qd, J=12.21, 4.55 Hz, 2H), 2.29-2.42(m, 1H), 2.54 (s, 3H), 3.47-3.60 (m, 2H), 3.99 (dd, J=11.37, 3.79 Hz,2H), 4.42 (q, J=7.24 Hz, 2H), 4.92 (tt, J=11.59, 4.20 Hz, 1H), 7.46 (s,1H).

Intermediate 41 Ethyl6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (125 mg,0.541 mmol) was dissolved in DMF (10 mL), followed by addition ofpotassium tert-butoxide (79 mg, 0.703 mmol). After stirring for 15minutes, 1,1-dimethylethyl (2-bromoethyl)carbamate (121 mg, 0.541 mmol)was added and the mixture was stirred at room temperature for 16 h. Thereaction mixture was concentrated to dryness. The crude residue wasdiluted with water (50 mL) and acidified with acetic acid. The contentswere extracted with DCM (4×50 mL). The combined organic layers werewashed with water, brine, dried over MgSO₄, filtered, and concentratedin vacuo. The crude residue was purified via silica gel chromatography(eluent: 0 to 50% EtOAc:Hex). The final product was obtained as 0.114 g(56%). LCMS E-S (M+H)=375.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.14(m, 4H), 1.15-1.20 (m, 2H), 1.27 (s, 7H), 1.41 (t, J=7.07 Hz, 3H),2.36-2.45 (m, 1H), 3.31-3.41 (m, 3H), 4.36-4.50 (m, 5H), 6.84 (t, J=5.81Hz, 1H), 7.65 (s, 1H), 8.24 (s, 3H).

Intermediate 42 Ethyl6-cyclopropyl-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 30 using 3-methyl-1-(4-pyridinyl)-1H-pyrazol-5-amine (310mg, 1.780 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (328 mg, 1.780mmol), benzene (50 mL), and acetic acid (25 mL). The final product wascollected as 3.71 (71% overall). LCMS E-S (M+H)=323.5 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.15-1.22 (m, 4H), 1.41 (t, J=7.07 Hz, 3H), 2.64-2.69 (m,4H), 4.47 (q, J=7.07 Hz, 2H), 7.74 (s, 1H), 8.27-8.36 (m, 2H), 8.66-8.71(m, 2H).

Intermediate 436-Cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To a solution of ethyl6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865mmol) in DMF (10 mL) was carefully added sodium hydride (29.1 mg, 1.211mmol). After 15 minutes stirring, iodoethane (0.077 mL, 0.951 mmol) wasadded and the mixture stirred at room temperature for 2 hr. Sodiumhydroxide (1 mL, 1.000 mmol) was added and the mixture allowed to stirat room temperature for 1 h. The contents were concentrated in vacuo.The crude residue was diluted with water (50 mL) and acidified withacetic acid. The contents were then extracted with DCM (4×50 mL). Thecombined organic layers were washed with water, brine, dried over MgSO4,filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography (eluent: hexanes to 100% EtOAc, then DCM to20% MeOH:DCM). The final product was collected as 90 mg (45%). LCMS E-S(M+H)=232.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.17 (m, 4H) 1.41 (t,J=7.33 Hz, 3H) 2.35-2.45 (m, 1H) 4.34-4.57 (m, 2H) 7.62 (s, 1H) 8.24 (s,1H) 13.83 (br. s., 1H). Regiochemical assignment supported by 2D HNMR.

Intermediate 446-Cyclopropyl-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The title compound was prepared as in the same manner as described forintermediate 43 using ethyl6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865mmol), sodium hydride (29.1 mg, 1.211 mmol), DMF (10 mL), 1-iodopropane(162 mg, 0.951 mmol), and NaOH (1 mL). The crude product was purified bysilica gel chromatography (eluent: 0 to 10% MeOH:DCM) to afford thefinal product as a solid, 90 mg (42%). Regiochemical assignmentsupported by 2D HNMR. LCMS E-S (M+H)=246.0 ¹H NMR (400 MHz, DMSO-d₆) δppm 13.83 (br s, 1H), 8.24 (s, 1H), 7.62 (s, 1H), 4.26 (t, 2H, J=7.2Hz), 2.37-2.40 (m, 2H), 1.83-1.89 (m, 2H), 1.07-1.11 (m, 4H), 0.77 (t,3H, J=7.2 Hz).

Intermediate 451-Amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To a solution of ethyl1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg,0.406 mmol) in ethanol (10 mL) was added sodium hydroxide (1 ml, 0.406mmol), and the mixture stirred at room temperature for 2 h. The solventwas removed in vacuo, and the residue diluted with EtOAc (30 mL) andwater (20 mL). The reaction mixture was acidified to pH 3 with citricacid. The phases were separated and the aq. phase extracted with EtOAc(4×20 mL). The combined organic layers were washed with water, driedover MgSO₄, filtered, and concentrated in vacuo. The final product wascollected as 0.075 g (84%). LCMS E-S (M+H)=219.5. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.00-1.13 (m, 4H), 2.27-2.45 (m, 1H), 6.36 (s, 2H), 7.60(s, 1H), 8.06 (s, 1H), 13.81 (br. s., 1H).

Intermediate 466-Cyclopropyl-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To a solution of ethyl6-cyclopropyl-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(200 mg, 0.696 mmol) in ethanol (5 mL) was added sodium hydroxide (2.088mL, 2.088 mmol), and the mixture stirred at room temperature for 30 min.The reaction mixture was concentrated in vacuo. The residue was dilutedwith water (30 mL) and then acidified with acetic acid. The contentswere extracted with DCM (3×30 mL). The combined organic layers werewashed with water, brine, dried over MgSO₄, filtered, and concentratedin vacuo. The final product was obtained as 0.17 g (94%). LCMS E-S(M+H)=260.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97-1.12 (m, 4H) 1.44 (d,J=6.57 Hz, 6H) 2.27-2.38 (m, 1H) 2.55 (s, 3H) 5.07 (quin, J=6.69 Hz, 1H)7.43 (s, 1H) 13.30-14.08 (m, 1H).

Intermediate 476-Cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 46 using ethyl6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(110 mg, 0.294 mmol), sodium hydroxide (1 mL, 0.294 mmol), and ethanol(10 mL) wherein the stir time was 16 h. The final product was collectedas 0.060 g (59%). LCMS E-S (M+H)=347.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.06-1.13 (m, 4H) 1.27 (s, 9H) 2.33-2.43 (m, 1H) 3.37 (q, J=5.81 Hz, 2H)4.44 (t, J=5.94 Hz, 2H) 6.84 (t, J=5.81 Hz, 1H) 7.62 (s, 5H) 8.24 (s,1H).

Intermediate 481-Cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 46 using ethyl1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(550 mg, 1.837 mmol), sodium hydroxide (3 ml, 3.00 mmol), and ethanol(30 mL) wherein the stir time was 1 h. The final product was collectedas 0.490 g (98%). LCMS E-S (M+H)=272.5 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.03-1.10 (m, 4H), 1.80-1.91 (m, 2H), 2.26-2.43 (m, 3H), 2.58 (s, 3H),2.59-2.71 (m, 2H), 5.35 (dq, J=8.59, 8.42 Hz, 1H), 7.44 (s, 1H), 13.73(br. s., 1H).

Intermediate 491-Cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 46 using ethyl1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(740 mg, 2.361 mmol), sodium hydroxide (4 ml, 4.00 mmol), and ethanol(30 mL), wherein the stir time was 1 h. The final product was collectedas 0.530 g (79%). LCMS E-S (M+H)=286.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.96-1.12 (m, 4H) 1.52-1.74 (m, 2H) 1.82-2.13 (m, 6H) 2.26-2.37 (m, 1H)2.55 (s, 3H) 5.17-5.30 (m, 1H) 7.43 (s, 1H) 13.70 (br. s., 1H).

Intermediate 506-Cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 46 using ethyl6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(240 mg, 0.796 mmol), sodium hydroxide (4 mL, 4.00 mmol), and ethanol(30 mL), wherein the stir time was 1 h. The final product was collectedas 0.210 g (96%). LCMS E-S (M+H)=274.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.05 (m, 4H) 1.70 (s, 9H) 2.33 (m, 1H) 2.51 (s, 3H) 7.46 (s, 1H) 13.70(br. s., 1H).

Intermediate 516-Cyclopropyl-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 46 using ethyl6-cyclopropyl-1-(4-pyridinyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(240 mg, 0.796 mmol), sodium hydroxide (4 mL, 4.00 mmol), and ethanol(30 mL), wherein the stir time was 1 h. The final product was collectedas 0.210 g (89%). LCMS E-S (M+H)=295.3.

Intermediate 526-Cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To an EtOH (10 mL) solution of ethyl6-cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(720 mg, 2.297 mmol) was added sodium hydroxide (6.89 mL, 6.89 mmol) andthe mixture heated at 70° C. for 1 hour. The solvent was removed invacuo and the residue was dissolved in 20 mL of water. The contents wereacidified with acetic acid, and extracted with EtOAc (4×30 mL). Thecombined organic extracts were washed with water, brine, dried overMgSO₄, filtered, and concentrated in vacuo. The final product wascollected as a solid, 0.560 g (85%). LCMS E-S (M+H)=286.3 ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.15-0.33 (m, 2H), 0.38 (dq, J=9.57, 4.89 Hz, 1H),0.50-0.65 (m, 1H), 0.90-1.10 (m, 4H), 1.27-1.42 (m, 1H), 1.57 (d, J=6.82Hz, 3H), 2.23-2.36 (m, 1H), 2.57 (s, 3H), 4.18 (dq, J=9.32, 6.83 Hz,1H), 7.44 (s, 1H), 12.79 (br. s., 1H).

Intermediate 531-cyclohexyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 52 using ethyl6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(820 mg, 2.5 mmol) and sodium hydroxide (7.51 mL, 7.51 mmol). The finalproduct was collected as a solid, 0.660 g (88%). LCMS E-S (M+H)=300.4 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.11 (m, 4H), 1.16-1.31 (m, 1H),1.36-1.55 (m, 2H), 1.70 (d, J=12.38 Hz, 1H), 1.80-1.98 (m, 6H), 2.32 (m,J=7.80, 7.80, 5.05, 4.86 Hz, 1H), 2.55 (s, 3H), 4.60-4.73 (m, 1H), 7.40(s, 1H), 13.71 (br. s., 1H).

Intermediate 546-Cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To an EtOH solution (10 mL) of ethyl6-cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(620 mg, 1.811 mmol) was added sodium hydroxide (5.43 mL, 5.43 mmol) andthe mixture heated at 70° C. for 1 hour. The solvent was removed invacuo and the residue was dissolved in 20 mL of water. The contents wereacidified with acetic acid, and extracted with EtOAc (4×30 mL). Thecombined organic extracts were washed with water, brine, dried overMgSO₄, filtered, and concentrated in vacuo to afford a minor amount ofproduct. The aqueous phase was concentrated in vacuo and the cruderesidue purified by reverse phase HPLC purification (eluent: 0% ACN/H₂O,0.1% TFA to 45% ACN/H₂O, 0.1% TFA). The isolated solid product wasconcentrated from toluene to afford the final product as 510 mg (90%).LCMS E-S (M+H)=315.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08 (d, J=6.57Hz, 4H), 2.10 (d, J=13.14 Hz, 2H), 2.30-2.42 (m, 3H), 2.55 (s, 3H),2.77-2.92 (m, 3H), 3.30 (br. s., 2H), 3.57 (d, J=12.13 Hz, 2H), 4.98 (m,J=11.78, 11.78, 3.85, 3.66 Hz, 1H), 7.46 (s, 1H), 9.87 (br. s., 1H).

Intermediate 556-Cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To an EtOH solution (30 mL) of ethyl6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(300 mg, 0.911 mmol) was added sodium hydroxide (1.82 mL, 1.82 mmol) andthe mixture stirred at room temperature for 16 h. The solvent wasremoved in vacuo and the residue was dissolved in 20 mL of water. Thecontents were acidified with acetic acid, and extracted with EtOAc (4×30mL). The combined organic extracts were washed with water, brine, driedover MgSO₄, filtered, and concentrated in vacuo to afford the finalproduct as 265 mg (97%). LCMS E-S (M+H)=302.4 ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.02-1.09 (m, 4H), 1.81 (dd, J=12.38, 2.27 Hz, 2H), 2.15 (qd,J=12.25, 4.42 Hz, 2H), 2.28-2.37 (m, 1H), 2.54 (s, 3H), 3.46-3.60 (m,2H), 3.89-4.02 (m, 2H), 4.91 (m, J=11.56, 11.56, 4.17, 4.04 Hz, 1H),7.42 (s, 1H), 13.73 (br. s., 1H).

Intermediate 56 (4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a solution of DMSO (10 mL) were sequentially added6-cyclopropyl-1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (270 mg, 0.779 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(178 mg, 1.169 mmol), and 1-hydroxy-7-azabenzotriazole (212 mg, 1.559mmol), and the mixture stirred at room temperature for 10 min. Next wasadded EDC (299 mg, 1.559 mmol) and N-methylmorpholine (0.343 mL, 3.12mmol), and reaction mixture was stirred at room temperature for 16 h.The contents were diluted with water (25 mL) and stirred for 10 min. Thesolid product was filtered off, dried, and collected as 0.290 g (98%).LCMS E-S (M+H)=381.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.15 (m, 4H),1.30 (s, 9H), 2.13 (s, 3H), 2.18-2.32 (m, 4H), 4.36 (d, J=4.80 Hz, 2H),4.42 (t, J=5.81 Hz, 2H), 5.90 (s, 1H), 6.85 (t, J=5.56 Hz, 1H), 7.44 (s,1H), 8.22 (s, 2H), 8.73 (t, J=4.67 Hz, 1H), 11.57 (br. s., 1H).

Example 981-(2-Aminoethyl)-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a solution of 1,1-dimethylethyl{2-[6-cyclopropyl-4-({[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]ethyl}carbamate(260 mg, 0.541 mmol) in DCM (15 mL) was added trifluoroacetic acid (3ml, 38.9 mmol) and the mixture stirred at room temperature for 2 h. Thecontents were concentrated in vacuo and the crude residue purified byreverse phase HPLC. (mobile phase: 10 to 70% ACN in H₂O, 0.1% NH₄OH).The final product was collected as 0.170 g (89%). LCMS E-S (M+H)=353.3¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.32 Hz, 4H), 2.13 (s, 3H),2.21 (s, 4H), 3.00 (t, J=6.19 Hz, 2H), 4.29-4.47 (m, 4H), 5.90 (s, 1H)7.43 (s, 1H), 8.22 (s, 1H), 8.75 (t, 1H).

Example 996-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-{2-[(methylsulfonyl)amino]ethyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a solution of1-(2-aminoethyl)-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide(120 mg, 0.315 mmol) in pyridine (2 mL) was added methanesulfonylchloride (0.025 mL, 0.315 mmol) and the reaction mixture stirred at roomtemperature for 16 hours. The reaction mixture was concentrated invacuo, diluted with water, and extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The crude product was purified by reverse phaseHPLC to afford a solid (25 mg). This solid was suspended in MeOH (1 mL)and treated with 4N HCl (1 mL). The solvent was removed under reducedpressure to afford the final product as a solid which was collected as15 mg (9%). LCMS E-S (M+H)=459.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.02-1.15 (m, 4H), 2.13 (s, 3H), 2.22 (s, 3H), 2.23-2.31 (m, 1H), 2.82(s, 3H), 3.45 (q, 2H), 4.36 (d, J=5.05 Hz, 2H), 4.49 (t, J=6.44 Hz, 2H),5.90 (s, 1H), 7.19 (s, 1H), 7.47 (s, 1H), 8.25 (s, 1H), 8.76 (t, J=4.93Hz, 1H), 11.56 (s, 1H).

Example 100N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid(200 mg, 0.748 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (142mg, 0.935 mmol), 1-hydroxy-7-azabenzotriazole (204 mg, 1.497 mmol), DMSO(10 mL), EDC (287 mg, 1.497 mmol), and N-methylmorpholine (0.329 mL,2.99 mmol). The final product was collected as 0.25 g (83%). LCMS E-S(M+H)=402.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93-1.12 (m, 4H), 1.42 (d,J=6.82 Hz, 6H), 2.12 (s, 3H), 2.22 (s, 4H), 2.36 (s, 3H), 4.34 (d,J=4.80 Hz, 2H), 4.90-5.11 (m, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.58 (s,1H), 11.51 (s, 1H.

Example 1016-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-cyclopropyl-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (91mg, 0.394 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (75 mg,0.493 mmol), 1-hydroxy-7-azabenzotriazole (107 mg, 0.788 mmol), DMSO (10mL), EDC (151 mg, 0.788 mmol), and N-methylmorpholine (0.173 mL, 1.577mmol). The final product was collected as 0.090 g (63%). LCMS E-S(M+H)=366.3 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07 (d, J=6.32 Hz, 4H),1.39 (t, J=7.20 Hz, 3H), 2.13 (s, 3H), 2.19-2.32 (m, 4H), 4.36 (d,J=4.80 Hz, 2H), 4.42 (q, J=7.07 Hz, 2H), 5.90 (s, 1H), 7.43 (s, 1H),8.21 (s, 1H), 8.75 (t, J=4.67 Hz, 1H), 11.57 (br. s., 1H).

Example 1026-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-cyclopropyl-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (90mg, 0.368 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70 mg,0.460 mmol), 1-hydroxy-7-azabenzotriazole (100 mg, 0.736 mmol), DMSO (10mL), EDC (141 mg, 0.736 mmol), and N-methylmorpholine (0.162 mL, 1.472mmol). The final product was collected as 0.118 g (84%). LCMS E-S(M+H)=380.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.78 (t, 3H), 0.99-1.16 (m,4H), 1.85 (d, J=7.33 Hz, 2H), 2.13 (s, 3H), 2.22 (s, 4H), 4.25-4.43 (m,4H), 5.90 (s, 1H), 7.43 (s, 1H), 8.21 (s, 1H), 8.75 (s, 1H), 11.57 (s,1H).

Example 1036-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-cyclopropyl-1-(2-methylpropyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (80 mg, 0.309 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(70.4 mg, 0.463 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.617 mmol),DMSO (10 mL), EDC (118 mg, 0.617 mmol), and N-methylmorpholine (0.136mL, 1.234 mmol). The final product was collected as 0.123 g (100%). LCMSE-S (M+H)=394.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93-1.12 (m, 4H), 1.42(d, J=6.82 Hz, 6H), 2.12 (s, 3H), 2.22 (s, 4H), 2.36 (s, 3H), 4.34 (d,J=4.80 Hz, 2H), 4.90-5.11 (m, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.58 (s,1H), 11.51 (s, 1H).

Example 1041-Amino-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (73mg, 0.335 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (76 mg,0.502 mmol), 1-hydroxy-7-azabenzotriazole (91 mg, 0.669 mmol), DMSO (10mL), EDC (128 mg, 0.669 mmol), and N-methylmorpholine (0.147 mL, 1.338mmol). The aq. phase was extracted with EtOAc (5×30 mL). The combinedEtOAc extracts were dried over MgSO₄, filtered, and concentrated invacuo. The final product was collected as 0.068 g (58%). LCMS E-S(M+H)=353.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99-1.14 (m, 4H), 2.13 (s,3H), 2.22 (s, 4H), 4.35 (d, J=4.80 Hz, 2H), 5.90 (s, 1H), 6.31 (s, 2H),7.41 (s, 1H), 8.04 (s, 1H), 8.74 (s, 1H), 11.58 (br. s., 1H).

Example 1051-Cyclobutyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (164 mg, 0.604 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(129 mg, 0.846 mmol), 1-hydroxy-7-azabenzotriazole (165 mg, 1.209 mmol),EDC (232 mg, 1.209 mmol), N-methylmorpholine (0.266 mL, 2.418 mmol), andDMSO (10 mL). The final product was collected as 0.240 g (98%). LCMS E-S(M+H)=406.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.06 Hz, 4H),1.85 (dd, J=9.35, 5.05 Hz, 3H), 2.12 (s, 4H), 2.16-2.28 (m, 6H),2.30-2.44 (m, 7H), 2.63 (d, J=19.96 Hz, 3H), 4.34 (d, J=4.29 Hz, 2H),5.31 (t, J=8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br. s., 1H),11.52 (br. s., 1H).

Example 1061-Cyclopentyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (160 mg, 0.561 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(119 mg, 0.785 mmol), 1-hydroxy-7-azabenzotriazole (153 mg, 1.121 mmol),EDC (215 mg, 1.121 mmol), N-methylmorpholine (0.247 mL, 2.243 mmol) andDMSO (10 mL). The final product was collected as 0.205 g (87%). LCMS E-S(M+H)=420.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.06 Hz, 4H),1.85 (dd, J=9.35, 5.05 Hz, 3H), 2.12 (s, 4H), 2.16-2.28 (m, 6H),2.30-2.44 (m, 7H), 2.63 (d, J=19.96 Hz, 3H), 4.34 (d, J=4.29 Hz, 2H),5.31 (t, J=8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br. s., 1H),11.52 (br. s., 1H).

Example 1076-Cyclopropyl-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-cyclopropyl-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (210 mg, 0.768 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(158 mg, 1.037 mmol), 1-hydroxy-7-azabenzotriazole (209 mg, 1.537 mmol),EDC (295 mg, 1.537 mmol), N-methylmorpholine (0.338 mL, 3.07 mmol), andDMSO (10 mL). The final product was collected as 0.280 g (89%). LCMS E-S(M+H)=408.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.02 (dddd, 4H), 1.69 (m,9H), 2.12 (s, 3H), 2.22 (m, 4H), 2.33 (s, 3H), 4.34 (d, J=4.80 Hz, 2H),5.87 (s, 1H), 7.04 (s, 1H), 8.55 (m, 1H), 11.51 (s, 1H).

Example 1086-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described forintermediate 56 using6-cyclopropyl-3-methyl-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (89 mg, 0.302 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(69.0 mg, 0.454 mmol), 1-hydroxy-7-azabenzotriazole (82 mg, 0.605 mmol),DMSO (20 mL), EDC (116 mg, 0.605 mmol), and N-methylmorpholine (0.133mL, 1.210 mmol). The final product was collected as 0.110 g (80%). LCMSE-S (M+H)=429.1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (br. s., 4H), 2.13(br. s., 3H), 2.25 (br. s., 4H), 3.34 (br. s., 3H), 4.37 (br. s., 2H),5.89 (br. s., 1H), 7.30 (br. s., 1H), 8.33 (br. s., 2H), 8.67 (br. s.,3H), 11.54 (br. s., 1H).

Example 1096-Cyclopropyl-1-(1-cyclopropylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Cyclopropyl-1-(1-cyclopropylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (186 mg, 0.652 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(160 mg, 0.847 mmol), 1-hydroxy-7-azabenzotriazole (177 mg, 1.304 mmol),EDC (250 mg, 1.304 mmol) and N-methylmorpholine (0.287 mL, 2.61 mmol)were dissolved in DMSO (10 mL) and stirred at room temperature for 3days. The reaction mixture was diluted with water (25 mL), stirred, andfiltered. The product was dried and collected as a solid, 0.200 g (73%).LCMS E-S (M+H)=420.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.14-0.30 (m, 2H),0.32-0.43 (m, 1H), 0.48-0.64 (m, 1H), 0.89-1.11 (m, 4H), 1.22-1.43 (m,1H), 1.55 (d, J=6.82 Hz, 3H), 2.11 (s, 3H), 2.18-2.28 (m, 4H), 2.37 (s,3H), 4.05-4.21 (m, 1H), 4.34 (d, J=4.80 Hz, 2H), 5.87 (s, 1H), 6.99 (s,1H), 8.59 (t, J=4.67 Hz, 1H), 11.51 (br. s., 1H).

Example 1101-Cyclohexyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using6-cyclopropyl-1-(1-cyclohexyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.501 mmol), and3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (123 mg, 0.651 mmol). Theproduct was collected as a solid, 0.190 g (87%). LCMS E-S (M+H)=434.2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.07 (m, 4H), 1.15-1.31 (m, 1H),1.36-1.52 (m, 2H), 1.68 (br. s., 1H), 1.77-1.99 (m, 6H), 2.11 (s, 3H),2.18-2.29 (m, 4H), 2.35 (s, 3H), 4.33 (d, J=4.80 Hz, 2H), 4.53-4.73 (m,1H), 5.87 (s, 1H), 6.96 (s, 1H), 8.58 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).

Example 1116-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

6-Cyclopropyl-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.477 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(117 mg, 0.620 mmol), 1-hydroxy-7-azabenzotriazole (130 mg, 0.954 mmol),EDC (183 mg, 0.954 mmol) and N-methylmorpholine (0.210 mL, 1.909 mmol)were suspended in DMSO (10 mL) and stirred at room temperature for 16 h.Next was added 25 mL of water, stirred for 10 minutes, and thenextracted with EtOAc (5×). The organic layers were concentrated in vacuoto afford 20 mg product. The aqueous phase was concentrated in vacuo andthe crude residue purified by reverse phase HPLC (mobile phase: 10-60%ACN in H₂O, 0.1% NH₄OH) to afford additional product. The final productwas collected as a solid, 0.100 g (47%). LCMS E-S (M+H)=449.0. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.97-1.05 (m, 4H), 1.79 (d, J=9.60 Hz, 2H),2.11 (s, 3H), 2.15 (d, J=8.34 Hz, 3H), 2.21 (s, 3H), 2.23-2.27 (m, 3H),2.35 (s, 3H), 2.91 (d, J=8.08 Hz, 2H), 4.33 (d, J=4.80 Hz, 2H),4.49-4.72 (m, 1H), 5.86 (s, 1H), 6.97 (s, 1H), 6.92-7.07 (m, 1H), 8.58(t, J=4.93 Hz, 1H), 11.50 (s, 1H).

Example 1126-Cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (150 mg, 0.498 mmol), and3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (98 mg, 0.647 mmol). Theproduct was collected as a solid, 0.170 g (78%). LCMS E-S (M+H)=436.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.14 (m, 4H), 1.79 (dd, J=12.63,2.27 Hz, 2H), 2.05-2.18 (m, 5H), 2.19-2.27 (m, 4H), 2.36 (s, 3H), 3.53(t, J=11.12 Hz, 2H), 3.98 (dd, J=11.49, 3.41 Hz, 2H), 4.33 (d, J=4.80Hz, 2H), 4.87 (m, J=11.53, 11.53, 4.11, 3.92 Hz, 1H), 5.87 (s, 1H), 6.99(s, 1H), 8.59 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).

Intermediate 57 Ethyl1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a solution of ethyl 2,4-dioxoheptanoate (446 mg, 2.397 mmol) inbenzene (5 mL) was added 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg,2.397 mmol), and the mixture was stirred at 62° C. for 18 h. Thereaction mixture was concentrated in vacuo and the residue purified bycolumn chromatography (Silica gel, gradient of 0 to 100% EtOAc/hexanes)to give 370 mg (56%) of product. LCMS E-S (M+H)=276.1. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.99-1.12 (m, 3H), 1.46-1.54 (m, 3H), 1.58-1.70 (m,6H), 1.82-1.96 (m, 2H), 2.91-3.02 (m, 2H), 4.51 (q, J=7.2 Hz, 2H),5.28-5.44 (m, 1H), 7.58-7.68 (s, 1H), 8.27-8.40 (s, 1H)

Intermediate 581-(1-Methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

To a solution of ethyl1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (180mg, 0.654 mmol) in ethanol (5 mL) and THF (1 mL) was added sodiumhydroxide (1.090 mL, 3.27 mmol), and the mixture was stirred at 40° C.for 1 h. The volatiles were removed under reduced pressure. The aqueousphase was acidified to pH 3 with aq. 1N HCl. The solid precipitateformed was collected by filtration and dried under high vacuum to give144 mg (89%) of product, which was used for next reaction withoutfurther purification. LCMS E-S (M+H)=248.1 ¹H NMR (400 MHz, DMSO-d₆) δppm 0.82-1.12 (m, 3H), 1.50 (d, J=6.6 Hz, 6H), 1.78 (m, 2H), 2.80-3.11(m, 2H), 5.09-5.38 (m, 1H), 7.47-7.72 (s, 1H), 8.18-8.46 (s, 1H), 13.82(s, 1H).

Intermediate 60 Ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate

The title compound was prepared in the same manner as intermediate 29using sodium metal (0.168 g, 7.32 mmol), 1-[4-(methyloxy)phenyl]ethanone(1 g, 6.66 mmol), and diethyl ethanedioate (0.903 mL, 6.66 mmol). Thecrude product was purified using column chromatography (0 to 100%EtOAc/hexanes) to give 0.95 g of product (57%). LCMS E-S (M+H)=250.9. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (m, 3H), 3.91 (s, 3H), 4.41 (q,J=6.65 Hz, 2H), 6.94-7.12 (m, 3H), 8.01 (d, J=8.59 Hz, 2H).

Intermediate 61 Ethyl1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a solution of ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (600mg, 2.397 mmol) in benzene (5 mL) was added1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and thereaction mixture was stirred at 62° C. overnight. The mixture wasconcentrated in vacuo and the residue was dissolved into acetic acid (3mL). The solution was stirred at reflux for 1 h and concentrated invacuo. The residue was purified using column chromatography (Silica gel,0 to 100% EtOAc/hexanes) to give 530 mg (65%) of product. LCMS E-S(M+H)=340.1 ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3H),1.61-1.71 (m, 6H), 3.88-3.96 (s, 3H), 4.55 (q, J=7.2 Hz, 2H), 5.46 (m,1H), 7.03-7.12 (m, 2H), 8.13-8.25 (m, 3H), 8.36-8.43 (m, 1H).

Intermediate 621-(1-Methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(200 mg, 0.589 mmol), Ethanol (4 mL) and THF (1 mL), and sodiumhydroxide (0.982 mL, 2.95 mmol). The final product was collected as 181mg (98%). LCMS E-S (M+H)=312.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.51-1.63 (m, 6H), 3.85 (s, 3H), 5.35 (m, 1H), 7.11 (d, J=9.1 Hz, 2H),8.15 (s, 1H), 8.18-8.25 (m, 2H), 8.33 (s, 1H), 13.95 (br. s., 1H).

Example 113N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (70 mg, 0.225 mmol), DMSO (3 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (63.6 mg, 0.337 mmol) HClsalt, N-methylmorpholine (0.099 mL, 0.899 mmol),1-hydroxy-7-azabenzotriazole (61.2 mg, 0.450 mmol), and EDC (86 mg,0.450 mmol). The final product was collected as 89 mg (89%). LCMS E-S(M+H)=446.5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (d, J=6.8 Hz, 6H),2.13 (s, 3H), 2.23 (s, 3H), 3.85 (s, 3H), 4.41 (d, J=4.8 Hz, 2H),5.20-5.48 (m, 1H), 5.91 (s, 1H), 7.11 (d, J=8.8 Hz, 2H), 8.11 (s, 1H),8.24 (d, J=8.8 Hz, 2H), 8.34 (s, 1H), 8.95 (m, 1H), 11.58 (s, 1H).

Intermediate 63 Ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate

The title compound was prepared in the same manner as intermediate 29using sodium metal (0.466 g, 20.26 mmol), 1-(4-pyridinyl)ethanone (1 g,6.66 mmol), and diethyl ethanedioate (2.388 mL, 17.62 mmol). The crudeproduct was purified using column chromatography (0 to 100%EtOAc/hexanes) to give 0.95 g of product (24%). LCMS E-S (M+H)=222.0 ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.37-1.55 (m, 3H), 4.43 (q, J=7.07 Hz,2H), 7.06-7.16 (m, 1H), 7.72-7.92 (m, 2H), 8.82-8.94 (m, 2H).

Intermediate 64 Ethyl1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

To a suspension of ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (442 mg,1.997 mmol) in benzene (5 mL) was added1-(1-methylethyl)-1H-pyrazol-5-amine (250 mg, 1.997 mmol), and thereaction mixture was stirred at 62° C. overnight. The reaction mixturewas concentrated in vacuo and the residue was purified using columnchromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give 270 mg(43%) of product. LCMS E-S (M+H)=311.3 ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.54 (t, J=7.2 Hz, 3H), 1.68 (d, J=6.6 Hz, 6H), 4.58 (q, J=7.1 Hz,2H), 5.41-5.60 (m, 1H), 8.04-8.19 (m, 2H), 8.29 (s, 1H), 8.44-8.55 (m,2H), 8.76-8.91 (m, 1H).

Intermediate 651-(1-Methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(100 mg, 0.322 mmol), ethanol (4 mL), THF (0.8 mL), and sodium hydroxide(0.537 mL, 1.611 mmol). The final product was collected as 88 mg (97%).LCMS E-S (M+H)=283.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (d, J=6.4 Hz,6H), 5.40 (m, 1H), 8.25 (d, J=5.6 Hz, 2H), 8.32 (s, 1H), 8.44 (s, 1H),8.79 (d, J=5.6 Hz, 2H), 14.12 (br. s., 1H).

Example 114N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (60 mg, 0.213 mmol), DMSO (2 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (60.1 mg, 0.319 mmol) HClsalt, N-methylmorpholine (0.093 mL, 0.850 mmol),1-hydroxy-7-azabenzotriazole (57.9 mg, 0.425 mmol), and EDC (81 mg,0.425 mmol). The final product was collected as 66 mg (74%). LCMS E-S(M+H)=446.5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56 (d, J=6.0 Hz, 6H),2.13 (br. s., 3H), 2.23 (br. s., 3H), 4.43 (m, 2H), 5.37 (m, 1H), 5.91(br. s., 1H), 8.15-8.34 (m, 3H), 8.44 (s, 1H), 8.78 (br. s., 2H), 9.00(br. s., 1H), 11.58 (br. s., 1H).

Intermediate 66 Ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate

Sodium metal (0.143 g, 6.21 mmol) was dissolved into ethanol (3 mL) andthe resulting solution was cooled with an ice bath. A mixture of1-(4-chlorophenyl)ethanone (0.756 mL, 5.65 mmol) and diethylethanedioate (0.766 mL, 5.65 mmol) were added dropwise, and the reactionmixture was stirred for 16 h. The reaction mixture was quenched with icewater (5 mL) and acidified to ˜pH 3 with 1N HCl. The precipitate wascollected by filtration and dried under high vacuum to give 1.39 g (97%)of product. LCMS E-S (M+H)=255.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.29(m, 3H), 4.27 (d, J=6.57 Hz, 2H), 7.60 (d, J=7.58 Hz, 2H), 8.02 (d,J=6.57 Hz, 2H).

Intermediate 67 Ethyl6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (610mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine(300 mg, 2.397 mmol), and acetic acid (4 mL). The crude product waspurified by column chromatography (Silica gel, eluent: 0 to 100%EtOAc/hexanes) to give 621 mg (75%) of product. LCMS E-S (M+H)=344.1. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.57 (m, 3H), 1.64-1.74 (m, 6H),4.56 (q, J=7.1 Hz, 2H), 5.46 (m, 1H), 7.49-7.55 (m, 2H), 8.15-8.18 (m,2H), 8.21 (s, 1H), 8.42 (s, 1H).

Intermediate 686-(4-Chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(400 mg, 1.163 mmol), Ethanol (6 mL), THF (1 mL), and added sodiumhydroxide (1.939 mL, 5.82 mmol) wherein the reaction time was 2 h. Thefinal product was collected as 330 mg (90%). LCMS E-S (M+H)=315.8. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.56 (d, J=6.8 Hz, 6H), 5.26-5.47 (m, 1H),7.62 (d, J=8.6 Hz, 2H), 8.20 (s, 1H), 8.28 (d, J=8.6 Hz, 2H), 8.38 (s,1H), 14.03 (s, 1H).

Example 1156-(4-Chlorophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (70 mg, 0.222 mmol), DMSO (2 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (62.7 mg, 0.333mmol), N-methylmorpholine (0.097 mL, 0.887 mmol),1-hydroxy-7-azabenzotriazole (60.3 mg, 0.443 mmol) and EDC (85 mg, 0.443mmol). The final product was collected as 77 mg (78%). LCMS E-S(M+H)=450.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (d, J=6.6 Hz, 6H),2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=4.6 Hz, 2H), 5.34 (quin, J=6.7Hz, 1H), 5.91 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 8.19 (s, 1H), 8.31 (d,J=8.6 Hz, 2H), 8.39 (s, 1H), 8.97 (t, J=4.7 Hz, 1H), 11.58 (s, 1H).

Intermediate 69 Ethyl 2,4-dioxo-4-(2-thienyl)butanoate

The title compound was prepared in the same manner as for intermediate66 using sodium metal (0.180 g, 7.85 mmol), 1-(3-thienyl)ethanone (0.9g, 7.13 mmol) and diethyl ethanedioate (0.967 mL, 7.13 mmol). Theproduct was collected as 1.41 g (87%). LCMS E-S (M+H)=226.9. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.30 (m, 3H), 4.29 (q, J=6.82 Hz, 2H), 6.96 (br. s.,1H), 7.60-7.81 (m, 2H), 8.74 (br. s., 1H).

Intermediate 70 Ethyl1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 2,4-dioxo-4-(3-thienyl)butanoate (542 mg,2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300mg, 2.397 mmol), and acetic acid (5 ml). The crude product was purifiedusing column chromatography (silica gel, eluent: 0 to 100%EtOAc/hexanes) to afford the product as 590 mg (78%). LCMS E-S(M+H)=315.8. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (t, J=6.8 Hz,3H), 1.66 (d, J=6.8 Hz, 6H), 4.56 (q, J=7.1 Hz, 2H), 5.43 (spt, J=6.7Hz, 1H), 7.47 (dd, J=5.1, 3.0 Hz, 1H), 7.84-7.95 (m, 1H), 8.08-8.18 (m,2H), 8.32-8.43 (m, 1H).

Intermediate 711-(1-Methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(400 mg, 1.268 mmol), Ethanol (5 mL) THF (1 mL), and sodium hydroxide(2.114 mL, 6.34 mmol). The final product was collected as 370 mg (100%).LCMS E-S (M+H)=287.9. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55 (d, J=6.8 Hz,6H), 5.34 (quin, J=6.6 Hz, 1H), 7.72 (dd, J=5.0, 3.0 Hz, 1H), 7.93 (dd,J=5.0, 1.3 Hz, 1H), 8.15 (s, 1H), 8.34 (s, 1H), 8.49 (dd, J=3.0, 1.3 Hz,1H), 13.97 (s, 1H).

Example 116N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (70 mg, 0.244 mmol), DMSO (2 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.9 mg, 0.365 mmol) HClsalt, N-methylmorpholine (0.107 mL, 0.974 mmol),1-hydroxy-7-azabenzotriazole (33.2 mg, 0.244 mmol) and EDC (93 mg, 0.487mmol). The final product was collected as 75 mg (73%). LCMS E-S(M+H)=422.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53 (d, J=6.8 Hz, 6H),2.13 (s, 3H), 2.23 (s, 3H), 4.41 (d, J=4.8 Hz, 2H), 5.30 (quin, J=6.6Hz, 1H), 5.91 (s, 1H), 7.71 (dd, J=5.0, 3.0 Hz, 1H), 7.92 (d, J=5.0 Hz,1H), 8.09 (s, 1H), 8.34 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.79-8.95 (m,1H), 11.58 (s, 1H).

Intermediate 72 Ethyl3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 64 using ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (766 mg,2.87 mmol), benzene (6 mL), and3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 2.87 mmol). Thecrude product was purified using column chromatography (Silica gel,eluent: 0 to 30% MeOH/DCM) to give 95 mg (10%) of product. LCMS E-S(M+H)=325.3. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.56 (m, 3H),1.61-1.73 (m, 6H), 2.77 (s, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.37-5.50 (m,1H), 8.02-8.16 (m, 3H), 8.76-8.83 (m, 2H).

Intermediate 733-Methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(36 mg, 0.111 mmol), Ethanol (2 ml) and sodium hydroxide (0.185 mL,0.555 mmol). The final product was collected as 26 mg 79%). LCMS E-S(M+H)=297.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54 (d, J=6.4 Hz, 6H),2.65 (s, 3H), 5.35 (m, 1H), 8.17 (s, 1H) 8.24 (m, 2H), 8.78 (m, 2H).

Example 117N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (20 mg, 0.067 mmol), DMSO (1 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol),N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole(18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol). The final productwas collected as 29 mg (100%). LCMS E-S (M+H)=431.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.52 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.46(s, 3H), 4.40 (d, J=5.0 Hz, 2H), 5.29 (quin, J=6.7 Hz, 1H), 5.89 (s,1H), 7.83 (s, 1H), 8.19 (d, J=6.1 Hz, 2H), 8.64-8.89 (m, 3H), 11.55 (br.s., 1H).

Intermediate 74 Ethyl1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 5,5-dimethyl-2,4-dioxohexanoate (392 mg,1.958 mmol), benzene (10 mL),1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (300 mg, 1.958 mmol),and acetic acid (2 mL). The crude product was purified by columnchromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 530mg (85%) of product. LCMS E-S (M+H)=318.3. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.43-1.52 (m, 12H), 1.84 (s, 9H), 2.67 (s, 3H), 4.50(q, J=7.07 Hz, 2H), 7.59 (s, 1H).

Intermediate 751,6-Bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To an EtOH solution (8 mL) of ethyl1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(528 mg, 1.663 mmol) was added sodium hydroxide (2.77 mL, 8.32 mmol),and the mixture was stirred for at room temperature for 2 h. Thevolatiles were removed under reduced pressure and the aqueous phase wasacidified using 1H HCl to ˜pH 3. The precipitate was filtered, washedwith water, and dried under high vacuum to give the product as 445 mg(92%). LCMS E-S (M+H)=289.4. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49 (s,9H), 1.76 (s, 9H), 2.51 (s, 3H), 7.51 (s, 1H).

Example 1181,6-Bis(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1,6-bis(1,1-dimethylethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (70 mg, 0.242 mmol), DMSO (2 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (68.5 mg, 0.363 mmol),N-methylmorpholine (0.106 mL, 0.968 mmol), 1-hydroxy-7-azabenzotriazole(65.9 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol). The final product wascollected as 91 mg (87%). LCMS E-S (M+H)=424.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (s, 9H), 1.74 (s,9H), 2.12 (s, 3H), 2.23 (s, 3H), 2.35 (s, 3H), 4.35 (d, J=4.80 Hz, 2H),5.88 (s, 1H), 7.15 (s, 1H), 8.61 (t, J=4.93 Hz, 1H), 11.52 (s, 1H).

Intermediate 76 Ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate

The title compound was prepared in the same manner as for intermediate66 using sodium metal (0.160 g, 6.95 mmol),1-[4-(methylthio)phenyl]ethanone (1.05 g, 6.32 mmol) and diethylethanedioate (0.856 mL, 6.32 mmol). The product was collected as 1.58 g(59%). LCMS E-S (M+H)=266.9. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.29-1.50 (m, 3H), 2.41-2.62 (m, 3H), 4.23-4.49 (m, 2H), 7.15-7.38 (m,2H), 7.89 (dd, J=8.72, 2.15 Hz, 2H).

Intermediate 77 Ethyl1-(1-methylethyl)-6-[4-(methylthio)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate(851 mg, 3.20 mmol), benzene (6 mL),1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and aceticacid (3 mL). The crude product was purified by column chromatography(Silica gel, eluent; 0 to 100% EtOAc/hexanes) to give 870 mg (63%) ofproduct. LCMS E-S (M+H)=433.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm1.47-1.57 (m, 3H), 1.66 (d, J=6.8 Hz, 6H), 2.58 (s, 3H), 4.56 (q, J=7.2Hz, 2H), 5.38-5.55 (m, 1H), 7.36-7.46 (m, 2H), 8.12-8.19 (m, 2H), 8.22(s, 1H), 8.40 (s, 1H).

Intermediate 78 Ethyl1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Oxone (1712 mg, 2.79 mmol) was added to a solution of ethyl1-(1-methylethyl)-6-[4-(methylthio)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(330 mg, 0.928 mmol) in acetone (6 mL) and water (2 mL), and thereaction mixture was stirred for 6 h. The reaction mixture was quenchedwith water (10 mL) and then neutralized with NaHCO₃ solution. Themixture was extracted with EtOAc (3×) and the combined extracts driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified using column chromatography (Silica gel, 0 to 100%EtOAc/hexanes) to give 295 mg (82%) of product. LCMS E-S (M+H)=388.1. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.54 (t, J=7.2 Hz, 3H), 1.67-1.69 (d,J=6.8 Hz, 6H), 3.14 (s, 3H), 4.58 (q, J=7.2 Hz, 2H), 5.48 (spt, J=6.7Hz, 1H), 8.06-8.18 (m, 2H), 8.29 (s, 1H), 8.39-8.44 (m, 2H), 8.47 (s,1H).

Intermediate 791-(1-Methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 58 using ethyl1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(260 mg, 0.671 mmol), Ethanol (4 mL), THF (1 mL) and sodium hydroxide(2N, 1.118 mL, 3.36 mmol). The final product was collected as 231 mg(96%). LCMS E-S (M+H)=360.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (d,J=6.8 Hz, 6H), 3.30 (s, 3H), 5.34-5.49 (m, 1H), 8.11 (d, J=8.6 Hz, 2H),8.30 (s, 1H), 8.44 (s, 1H), 8.51 (d, J=8.6 Hz, 2H).

Example 119N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (90 mg, 0.250 mmol), DMSO (2 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70.9 mg, 0.376 mmol),N-methylmorpholine (0.110 mL, 1.002 mmol), 1-hydroxy-7-azabenzotriazole(68.2 mg, 0.501 mmol) and EDC (96 mg, 0.501 mmol). The final product wascollected as 106 mg (85%). LCMS E-S (M+H)=494.2. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.56 (d, J=5.6 Hz, 6H), 2.13 (br. s., 3H), 2.23 (br. s.,3H), 4.42 (m, 2H), 5.36 (br. s., 1H), 5.91 (br. s., 1H), 8.11 (d, J=7.3Hz, 2H), 8.27 (br. s., 1H), 8.39-8.64 (m, 3H), 9.01 (br. s., 1H), 11.58(br. s., 1H).

Intermediate 80 Ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate

The title compound was prepared in the same manner as for intermediate66 using sodium metal (0.404 g, 17.58 mmol), 1-(4-bromophenyl)ethanone(3.5 g, 17.58 mmol), and diethyl ethanedioate (2.384 mL, 17.58 mmol).The product was collected as 5.1 g (97%). LCMS E-S (M+H)=299.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.22-1.37 (m, 3H), 4.25 (d, J=6.57 Hz, 2H),7.72 (m, 2H), 7.92 (m, 2H).

Intermediate 81 Ethyl6-(4-bromophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 4-(4-bromophenyl)-2,4-dioxobutanoate (956mg, 3.20 mmol), benzene (10 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine(400 mg, 3.20 mmol), and acetic acid (4 mL). The crude product waspurified using column chromatography (Silica gel, eluent: 0 to 100%EtOAc/hexanes) to give 1.1 g (89%) of product. LCMS E-S (M+H)=388.1. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.49-1.57 (t, J=67.2 Hz, 3H),1.63-1.74 (d, J=6.8 Hz 6H), 4.56 (q, J=7.2 Hz, 2H), 5.46 (spt, J=6.7 Hz,1H), 7.65-7.71 (m, 2H), 8.04-8.15 (m, 2H), 8.21 (s, 1H), 8.42 (s, 1H).

Intermediate 821-(1-Methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

To a 5-mL microwave vial were added ethyl6-(4-bromophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(80 mg, 0.206 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56.0 mg,0.288 mmol), 1,4-dioxane (2 mL) and sodium carbonate (0.206 mL, 0.412mmol), and the mixture was degassed with nitrogen for 10 min. Next addedPdP(Ph₃)₄ (19.05 mg, 0.016 mmol) and the vial was sealed. The reactionmixture was irradiated (microwave) at 120° C. overnight. The reactionmixture was filtered and concentrated in vacuo. The residue was purifiedusing reverse-phase HPLC to give 25 mg (35%) of product. LCMS E-S(M+H)=348.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.58 (d, J=6.8 Hz, 6H),5.38 (quin, J=6.6 Hz, 1H), 7.81 (d, J=8.3 Hz, 2H), 8.14-8.30 (m, 4H),8.36 (s, 1H).

Example 120N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (20 mg, 0.058 mmol), DMSO (1 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (16.29 mg, 0.086 mmol),N-methylmorpholine (0.025 mL, 0.230 mmol), 1-hydroxy-7-azabenzotriazole(15.67 mg, 0.115 mmol) and EDC (22.07 mg, 0.115 mmol). The final productwas collected as 12 mg (43%). LCMS E-S (M+H)=482.0. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.56 (d, J=6.4 Hz, 6H), 2.14 (s, 3H), 2.24 (s, 3H), 4.42(d, J=4.8 Hz, 2H) 5.27-5.47 (m, 1H), 5.91 (s, 1H), 7.79 (d, J=8.3 Hz,2H), 8.04 (br. s., 1H), 8.15-8.21 (m, 1H), 8.27 (d, J=8.3 Hz, 2H),8.35-8.42 (m, 1H), 8.99 (t, J=4.8 Hz, 1H), 11.58 (br. s., 3H).

Intermediate 83 Ethyl1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate(327 mg, 1.305 mmol), benzene (8 mL),1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (200 mg, 1.305 mmol),and acetic acid (2 mL). The crude product was purified using columnchromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give0.41 g (85%) of product. LCMS E-S (M+H)=368.1. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.81 (s, 9H), 2.55 (s, 3H), 7.11 (d, J=8.84 Hz, 2H), 7.89 (s, 1H),8.16 (d, J=8.84 Hz, 2H).

Intermediate 841-(1,1-Dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

The title compound was prepared in the same manner as described forintermediate 75 using ethyl1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(400 mg, 1.089 mmol), 3N sodium hydroxide (1.814 mL, 5.44 mmol), andEtOH (6 mL). The product was collected as 347 mg (94%). LCMS E-S(M+H)=340.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81 (s, 9H), 2.55 (s, 3H),7.11 (d, J=8.84 Hz, 2H), 7.89 (s, 1H), 8.16 (d, J=8.84 Hz, 2H).

Example 1211-(1,1-Dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

To a solution of1-(1,1-dimethylethyl)-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (70 mg, 0.206 mmol) in DMSO (1 mL) were added3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol),N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole(18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol), and the mixturewas stirred overnight at room temperature. The reaction mixture wasquenched with water (10 mL), stirred for 10 min., and filtered. Thecontents were dried under high vacuum and collected as 71 mg (71%). LCMSE-S (M+H)=474.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79 (s, 9H), 2.12 (s,3H), 2.25 (s, 3H), 2.39 (s, 3H), 3.33 (s, 1H), 4.38 (d, J=4.80 Hz, 2H),5.88 (s, 1H), 7.10 (d, J=8.84 Hz, 2H), 7.61 (s, 1H), 8.16 (d, J=8.84 Hz,2H), 8.70 (s, 1H), 11.53 (s, 1H).

Intermediate 85 Ethyl1-(1,1-dimethylethyl)-3-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Trifluoromethanesulfonic anhydride (0.457 mL, 2.70 mmol) was addeddropwise to a solution of ethyl1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(500 mg, 1.803 mmol) in pyridine (10 mL), and the reaction mixture wasstirred at room temperature for 16 h. The contents were diluted withEtOAc and washed with saturated NaHCO₃, and then brine. The organiclayer was dried over MgSO₄, filtered, and concentrated in vacuo. Thecrude residue was purified via silica gel chromatography (0% to 100%DCM:Hex) to afford the final product as a solid, 670 mg (91%). LCMS E-S(M+H)=410.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38 (t, J=7.07 Hz, 3H),1.71 (s, 9H), 2.58 (s, 3H), 4.46 (q, J=7.07 Hz, 2H), 7.63 (s, 1H).

Intermediate 86 Ethyl1-(1,1-dimethylethyl)-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Ethyl1-(1,1-dimethylethyl)-3-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(100 mg, 0.244 mmol), 3-pyridinylboronic acid (39.0 mg, 0.318 mmol), aq.saturated NaHCO₃ (1 mL) and 1,4-dioxane (3 mL) were degassed withnitrogen (10 min) followed by addition of PdCl₂(dppf)-CH₂Cl₂ adduct(9.97 mg, 0.012 mmol). The sealed mixture was irradiated (microwave) at120° C. for 40 min. The reaction mixture was diluted with EtOAc andfiltered. The filtrate was concentrated in vacuo and the crude residuewas purified by silica gel chromatography (0 to 100% EtOAc/hexanes). Thefinal product was collected as a solid, 72 mg (87%). LCMS E-S(M+H)=339.3. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.57 (m, 3H), 1.90 (s,9H), 2.72 (s, 3H), 4.45-4.64 (m, 2H), 7.47 (dd, J=8.08, 4.80 Hz, 1H),8.03 (s, 1H), 8.46 (dt, J=8.08, 2.02 Hz, 1H), 8.72 (dd, J=4.80, 1.52 Hz,1H), 9.43 (d, J=1.52 Hz, 1H).

Intermediate 871-(1,1-Dimethylethyl)-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

Ethyl1-(1,1-dimethylethyl)-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(68 mg, 0.201 mmol) was suspended in ethanol (2 mL) followed by additionof sodium hydroxide (0.335 mL, 1.005 mmol). The mixture was stirred atroom temperature for 2.5 h. The mixture was concentrated and the residuewas diluted with water (1 mL) and acidified to pH 3 using 1N HCl. Theprecipitate was collected by filtration and further dried under highvacuum to give the product as an HCl salt, 60 mg (86%). LCMS E-S(M+H)=311.5. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.82 (s, 9H), 2.60 (s, 3H),7.60 (dd, J=7.96, 4.67 Hz, 1H), 8.08 (s, 1H), 8.57 (dt, J=8.34, 1.89 Hz,1H), 8.70 (dd, J=4.80, 1.52 Hz, 1H), 9.39 (d, J=1.52 Hz, 1H), 14.03 (br.s., 1H).

Example 1221-(1,1-Dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 121 using1-(1,1-dimethylethyl)-3-methyl-6-[3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (58 mg, 0.167 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone(47 mg, 0.251 mmol), N-methylmorpholine (0.092 mL, 0.836 mmol),1-hydroxy-7-azabenzotriazole (46 mg, 0.334 mmol), EDC (64 mg, 0.334mmol), and DMSO (1 mL). The product was collected as 73 mg (96%). LCMSE-S (M+H)=445.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.81 (s, 9H), 2.12 (s,3H), 2.25 (s, 3H), 2.42 (s, 3H), 4.39 (d, J=5.05 Hz, 2H), 5.89 (s, 1H),7.59 (dd, J=8.08, 4.80 Hz, 1H), 7.78 (s, 1H), 8.55 (dt, J=8.15, 1.86 Hz,1H), 8.68 (dd, J=4.80, 1.52 Hz, 1H), 8.74 (t, J=5.05 Hz, 1H) 9.38 (d,J=1.77 Hz, 1H), 11.54 (s, 1H).

Example 1233-Bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

3-Bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (93 mg, 0.258 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinonehydrochloride (64 mg, 0.336 mmol), HOBT (60 mg, 0.387 mmol) and EDC (74mg, 0.387 mmol) were suspended in DMSO (14 mL) and stirred at roomtemperature for 10 minutes, after which time DIEA (0.9 ml, 5.16 mmol)was added. After stirring for 2 h, 4-methylmorpholine (1 ml, 9.04 mmol)was added. The reaction mixture was stirred first at room temperaturefor 21 h, and then at 80° C. (aluminum heating block) for 31 h. Thereaction mixture was cooled to room temperature and then added dropwiseto a cold, slightly basic solution (pH ˜8-10) of water (100 mL) and 1NNa₂CO₃ (8 mL). After stirring for 20 min., the contents were extractedwith EtOAc (2×100 mL). The combined organic layers are washed withbrine, dried over Na₂SO₄, filtered, and concentrated to a residue. Thecrude residue was dissolved in 10% MeOH/DCM and purified by silica gelchromatography (eluent: 10-95% gradient EtOAc/Hexanes and then 10% (5%NH₄OH/MeOH)/DCM and EtOAc, 10-90% gradient). The product was collectedas an off-white solid. (35 mg, 27%). LCMS E-S (M+H)=494.1/496.0. ¹H NMR(400 MHz, CHLOROFORM-d) δ 11.58 (br. s., 1H), 8.11 (dd, J=1.89, 7.71 Hz,2H), 7.68 (br. s., 1H), 7.60 (br. s., 1H), 7.44-7.53 (m, 3H), 5.92 (s,1H), 5.42 (quin, J=6.69 Hz, 1H), 4.63 (br. s., 1H), 2.41 (br. s., 3H),2.11 (br. s., 3H), 1.62 (d, J=6.57 Hz, 6H).

Intermediate 883-Bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

Ethyl3-bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate(112 mg, 0.288 mmol) was suspended in THF (0.5 mL) and ethanol (1.5 mL),followed by addition of 3N NaOH (150 μl, 0.433 mmol). The reactionmixture was stirred at 55° C. for 3 hours, and then allowed to cool toroom temperature. The reaction mixture was diluted with water (1.5 mL),cooled in an ice bath, and acidified with 1N HCl in a dropwise manner.The mixture was extracted with EtOAc. The organic layer was separatedand concentrated in vacuo to afford a solid that dried on the highvacuum 3 hours. The product was collected as a pale yellow solid (93.6mg, 90%). LCMS E-S (M+H)=360.0/362.2. ¹H NMR (400 MHz, MeOD) 68.22 (dd,J=1.52, 8.08 Hz, 2H), 8.05 (s, 1H), 7.48-7.59 (m, 3H), 5.47 (quin,J=6.76 Hz, 1H), 1.63 (d, J=6.82 Hz, 6H)

Intermediate 89 Ethyl3-bromo-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Ethyl1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (120mg, 0.388 mmol), was suspended in acetic acid (2 mL) followed byaddition of bromine (26 μl, 0.504 mmol). The reaction mixture wasstirred with heating at 80° C. After 1 h, a second portion of brominewas added (26 μl, 0.504 mmol) and the reaction mixture heated at 80° C.for an additional 2 h. After cooling to room temperature, the solutionwas added to a saturated aqueous solution of sodium bicarbonate (6 mL)and extracted with dichloromethane (2×10 mL) The combined organic layerswere concentrated in vacuo. The crude product was purified by silica gelchromatography (eluent: EtOAc/Hexanes, 0-50% gradient). The product wascollected as a white powder (112 mg, 74%). LCMS E-S (M+H)=388.0/390.2.¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (dd, J=1.52, 8.08 Hz, 2H), 8.00(s, 1H), 7.48-7.58 (m, 3H), 5.47 (quin, J=6.76 Hz, 1H), 4.58 (q, J=7.16Hz, 2H), 1.65 (d, J=6.82 Hz, 6H), 1.52 (t, J=7.20 Hz, 3H).

Intermediate 90 Ethyl1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

The title compound was prepared in the same manner as described forintermediate 61 using ethyl 2,4-dioxo-4-phenylbutanoate (5 g, 22.7mmol), 1-(1-methylethyl)-1H-pyrazol-5-amine (2.84 g, 22.7 mmol), benzene(70 mL), and acetic Acid (44 mL) The crude product was purified bysilica gel chromatography (eluent: 0 to 100% EtOAc/hexanes) to give 6.72g (95%) as a pale yellow solid. LCMS E-S (M+H)=310.5. ¹H NMR (400 MHz,DMSO-d₆) δ 8.39 (s, 1H), 8.17-8.28 (m, 3H), 7.49-7.64 (m, 3H), 5.38(quin, J=6.69 Hz, 1H), 4.49 (q, J=7.07 Hz, 2H), 1.57 (d, J=6.57 Hz, 6H),1.44 (t, 3H).

Example 124N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

1-(1-Methylethyl)-3-nitro-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid (24 mg, 0.074 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinonehydrochloride (18 mg, 0.096 mmol), HOAT (17 mg, 0.110 mmol) and EDC (21mg, 0.110 mmol) were suspended in DMSO (800 μL) and the reaction mixturestirred at room temperature. Next added 4-methylmorpholine (41 μl, 0.368mmol), and the reaction was stirred at room temperature for 16 h. Thereaction mixture was added dropwise to cold, slightly basic solution ofwater (3 mL) and 1N Na₂CO₃ (0.5 mL). After stirring for 20 min., theprecipitated solids were collected via vacuum filtration and washed withwater. The solid was dried on the high vacuum (72 h). The product, wascollected as an off-white powder (28 mg, 82%). LCMS E-S (M+H)=461.1. ¹HNMR (400 MHz, DMSO-d₆) δ 9.01 (br. s., 1H), 8.42 (s, 1H), 8.02 (ddd,J=1.14, 4.99, 7.77 Hz, 2H), 7.99 (s, 1H), 7.86 (td, J=1.26, 7.58 Hz,1H), 7.72-7.77 (m, 1H), 5.90 (s, 1H), 5.04 (quin, J=6.69 Hz, 1H), 4.41(d, J=4.55 Hz, 1H), 3.34 (s, 2H), 2.22 (s, 3H), 2.12 (s, 3H), 1.49 (d,J=6.57 Hz, 6H).

Intermediate 911-(1-Methylethyl)-6-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylicacid

Ethyl1-(1-methylethyl)-3-nitro-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylatewas suspended in THF (0.5 ml) and ethanol (1 mL), followed by additionof 3N NaOH aq (50 μL). The reaction mixture was heated at 55° C. for 1h, and then allowed to cool to room temperature. The volatiles wereremoved in vacuo and the residue was dissolved in water (1.5 mL). Thereaction mixture was cooled in an ice bath and acidified by dropwiseaddition of 1N HCl. After stirring for 20 minutes, the precipitatedsolids were collected by vacuum filtration dried under high vacuumovernight for 16 h. The product was collected as a white solid (24.5 mg,76%). LCMS E-S (M+H)=327.2. ¹H NMR (400 MHz, DMSO-d₆) δ 14.14 (br. s.,1H), 8.43 (s, 1H), 8.04 (dd, J=1.14, 7.96 Hz, 1H), 7.98-8.02 (m, J=1.26Hz, 2H), 7.86 (td, J=1.26, 7.58 Hz, 1H), 7.72-7.80 (m, 1H), 5.09 (qd,J=6.57, 6.74 Hz, 1H), 1.51 (d, J=6.57 Hz, 6H).

Intermediate 92 Ethyl1-(1-methylethyl)-6-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate

Ethyl1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (120mg, 0.388 mmol) was dissolved in concentrated nitric acid (1.7 mL)followed by addition of concentrated sulfuric acid (0.200 mL), and thereaction mixture was stirred at room temperature. After 40 min., thereaction mixture was cooled in an ice bath and with stirring was dilutedwith water (3 mL) and then slowly with saturated Na₂CO₃ (1 mL). Thereaction mixture was extracted with EtOAc (2×6 mL). The combined organiclayers were concentrated in vacuo and the crude product purified bysilica gel chromatography (eluent: EtOAc/Hexanes, 0-70% gradient). Theproduct, was collected as a white solid (35 mg, 26%). LCMS E-S(M+H)=355.2. ¹H NMR (400 MHz, CHLOROFORM-d) 8.46 (s, 1H), 7.99 (s, 1H),7.94 (dd, J=1.14, 7.96 Hz, 1H), 7.76-7.81 (m, 1H), 7.73 (td, J=1.26,7.58 Hz, 1H), 7.59-7.66 (m, 1H), 5.25 (ddd, J=6.57, 6.69, 13.52 Hz, 1H),4.51-4.59 (m, 2H), 1.61 (d, J=6.82 Hz, 6H), 1.52 (t, J=7.07 Hz, 3H).

Example 125N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide

The title compound was prepared in the same manner as described inexample 109 using1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid(70 mg, 0.283 mmol), DMSO (3 mL),3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (80 mg, 0.425 mmol),N-methylmorpholine (0.124 mL, 1.132 mmol), 1-hydroxy-7-azabenzotriazole(77 mg, 0.566 mmol), and EDC (109 mg, 0.566 mmol). The collected solidwas washed with water and methanol and dried under high vacuum to give73 mg (68%) of product. LCMS E-S (M+H)=382.3 ¹H NMR (400 MHz, DMSO-d₆) δppm 0.82-1.10 (m, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.77 (m, 2H), 2.13 (s,3H), 2.21 (s, 3H), 2.85 (t, J=7.6 Hz, 2H), 4.36 (d, J=4.8 Hz, 2H), 5.20(m, 1H), 5.90 (s, 1H), 7.38-7.58 (m, 1H), 8.26 (s, 1H), 8.73 (t, J=4.7Hz, 1H), 11.57 (br. s., 1H).

Intermediate 93 3-(Aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone

Step 1

2,4-Hexanedione (2.283 g, 20 mmol) and cyanacetamide (1.682 g, 20.00mmol) were added to ethanol (20 mL). The contents were initiallyheterogenous, but gradually dissolved upon reaching ca. 70° C. Nextadded piperidine (1.976 mL, 20.00 mmol) and stirred with warming toreflux. After 30 min, the heterogenous contents were removed fromheating and allowed to stir with cooling to room temperature. Thecontents were filtered in vacuo to afford a light yellowish coloredsolid and yellow filtrate. The collected solid filter cake was copiouslywashed with water which removed the yellow color. The final product wascollected as fine white crystalline solid (1.66 g after drying). LCMSE-S (M+H)=163.2. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (t, J=7.58Hz, 3H) 2.47 (s, 3H) 2.71 (q, J=7.58 Hz, 2H), 6.12 (s, 1H).

Step 2

To a stirred solution of6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.462 g, 9.01mmol) in Methanol (50 mL), cooled to 0° C. were addeddi-tertbutoxycarbonyl anhydride (4.19 mL, 18.03 mmol) and nickel(II)chloride.hexahydrate (0.214 g, 0.901 mmol). Sodium borohydride (2.387 g,63.1 mmol) was added portionwise over 30 min, then the mixture wasallowed to warm to room temperature and stirred overnight. Additionalsodium borohydride (2.387 g, 63.1 mmol) was added and the reactionstirred overnight again. Diethylenetriamine (0.979 mL, 9.01 mmol) wasadded, and the reaction mixture was stirred for 30 min. at roomtemperature. The solvent was evaporated, and the residue was dissolvedin ethyl acetate (20 mL) and extracted with sodium bicarbonate (2×10mL). The organics were dried over sodium sulfate, and concentrated. Theresidue was dissolved in chloroform (25 mL) and TFA (3.47 mL, 45.1 mmol)was added. The reaction was heated to 50° C. for 3 h, then cooled toroom temperature and concentrated. The reaction mixture was concentratedin vacuo and the crude product was purified by reverse phase HPLC(eluent; 0-30% gradient ACN in H2O, 0.1% TFA) to afford the titlecompound (TFA salt, 1.37 g, 54.1% yield) as a white solid. LC-MS (ES)m/z=167 [M+H]+. ¹H NMR (400 MHz, DMSO-d) δ ppm 1.12 (t, J=7.58 Hz, 3H),2.20 (s, 3H), 2.44 (q, J=7.58 Hz, 2H), 3.78-3.83 (m, 2H), 6.01 (s, 1H),7.75-7.9 (br s, 3H), 11.86 (s, 1H).

Intermediate 94 3-(Aminomethyl)-5-fluoro-4,6-dimethyl-2(1H)-pyridinone

Step 1

2,4-Pentanedione (12 g, 120 mmol) was suspended in deuterated MeCN (39mL), to which was added Selectfluor (44.7 g, 120 mmol) in one portion.The resulting paste was then heated in an oil bath to 50° C. After 5min, an exotherm was observed, and the mixture was removed from the oilbath. The mixture was then heated at 50° C. for 1 h. The mixture wasthen aged at room temperature for 16 h, and then distilled under vacuum.The desired product distilled at 40-60° C. at 10-15 torr and wascollected as a light yellowish liquid (1.8 mL, 1.95 g). A less purefraction (ca. 80%) distilled at 25-35° C. at 15-20 ton, and wascollected as a light yellowish liquid (3.33 g). ¹H NMR (400 MHz,ACETONITRILE-d₃) δ ppm 2.24 (s, 3H), 2.26 (s, 3H), 5.46 (d, J=48.0 Hz,1H).

Step 2

A mixture of 3-fluoro-2,4-pentanedione (247 mg, 2.10 mmol),cyanoacetamide (176 mg, 2.1 mmol, 1 equiv) and piperidine (0.21 mL, 2.1mmol, 1 equiv) in 3 mL of EtOH was heated at 85° C. for 16 h, resultingin a clear but dark brown solution. The mixture was concentrated invacuo. The residue was taken up in 2 mL of 1N HCl to give a suspension,which was filtered. The tan solids collected were dried under vacuum togive the desired product as 80 mg. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm2.33 (s, 3H), 2.42 (s, 3H).

Step 3

5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.0 g,6.02 mmol) was suspended in 50 mL of HOAc at room temperature to give adark brownish solution. NaOAc (1.0 g, 12.3 mmol, 2 equiv), PtO₂ (20 mg)and 5% Pd/C (1.3 g) were charged into a 500 mL Parr bottle, followed bywetting with some acetic acid under nitrogen. The substrate solution wasthen added, and rinsed with another 50 mL of acetic acid. The mixturewas hydrogenated under a pressure of 40 psi. There was initial drop ofhydrogen pressure and the vessel was refilled. The mixture washydroganted for 6 h. The mixture was filtered through Celite, andconcentrated in vacuo to give a solid residue, which was suspended in 6mL of conc. HCl to give a paste. The paste was filtered, and the cakewas washed with 1 mL of conc HCl (in duplicate). The filtrate wasconcentrated in vacuo. The solid residue dissolved in 0.4 mL of conc.HCl and 6 mL of EtOH as a suspension, which was stored in the freezerfor 2 h, followed by filtration. The cake was washed with 2 mL of coldEtOH (in duplicate). The solids were dried under vacuum at roomtemperature for 18 h to give the title compound as a cream-colored solid(1.03 g). LC-MS (ES) m/z=171 [M+H]⁺ and a dominant peak at 154. ¹H NMR(400 MHz, DMSO-d₆) δ ppm, 2.20 (d, J=3.0 Hz, 3H), 2.22 (d, J=2.0 Hz,3H), 3.83 (q, J=5.2 Hz, 2H), 7.99 (br. s., 3H), 11.99 (br. s., 1H).

Assay Protocol

Part A. Compound Preparation

-   -   1. Prepare 10 mM stock of compounds from solid in 100% DMSO.    -   2. In a 384-well Greiner plate (Cat #781280), plate compounds in        columns 1 and 13.    -   3. Set up a Multiprobe instrument to do an 11 point serial        dilution (1:3 dilution, columns 6 and 18 are DMSO controls).    -   4. Stamp 100 nL of compound from the dilution plate into        reaction plates (Corning, 384-well, Cat#3706) using the        Hummingbird.        Part B. Reagent Preparation    -   1. Prepare 2× assay buffer mix with final concentrations of 50        mM Tris pH 8, 5 mM MgCl₂, 4 mM DTT, 0.00185% Tween-20, and 7        μg/ml Hela nucleosomes (GRITS36431).    -   2. Prepare 2×EZH2 (GRITS37108) enzyme mix in assay buffer with a        final enzyme concentration of 10 nM.    -   3. Prepare 2× mix of hot and cold SAM in ddH₂O with final        concentrations of 0.24 μM cold SAM (Sigma) and 0.02 μCi/μL        ³H-SAM (Perkin Elmer).    -   4. Prepare 500 μM SAH quench solution in ddH₂0 with 5-10 drops        of concentrated HCl to dissolve.    -   5. Prepare 6 mg/ml RNA binding SPA beads (Perkin Elmer)        suspended in 0.2 M Citric Acid, pH 2.2

Reagent Stock 2x [Final] [Final] Mix 1. Assay Buffer Mix Tris pH 8 1000mM  100 mM   50 mM MgCl₂ 1000 mM   10 mM   5 mM DTT 1000 mM   8 mM   4mM Tween-20  1% 0.0037% 0.00185% Hela  492 μg/ml   14 μg/ml   7 μg/mlnucleosomes In ddH₂0 Mix 2. Enzyme Mix EZH2 1351 nM   20 nM   10 nMGRITS37108 In Mix 1. Buffer Mix 3. SAM Substrate Mix, 500 nM total SAMCold SAM  100 μM 0.48 μM 0.24 μM ³H-SAM   0.5 μCi/μL5 0.04 μCi/μL 0.02μCi/μL 78 Ci/mmol DMSO 100%    2%     1% In ddH₂0 *Assay is run atapparent substrate K_(m) for SAM and nucleosomes.Part C. Assay Reaction in 384-Well Corning 3706 PlatesIn Reaction Plates Stamped with 100 nL Compound,

-   -   1. Dispense 5 μL no enzyme control (assay buffer mix) to column        18 of plates.    -   2. Dispense 5 μL of enzyme mix to the remaining wells in the        plate. Centrifuge plate to mix and incubate at room temperature        for 30 minutes.    -   3. Dispense 5 μL of substrate mix to all wells to initiate the        reactions. Centrifuge plate to mix and incubate at room        temperature for 2 hours.    -   4. Quench the reactions with 10 μL of 500 μM SAH solution (250        μM final).    -   5. Dispense 10 μL of 6 mg/ml RNA binding SPA beads prepared in        0.2 M citric acid, pH 2.2 using the Evolution instrument.        Continuously shake the beads while adding to plates to prevent        beads from settling.    -   6. Seal the plates with Perkin Elmer top seals and allow the        beads to equilibrate in the plate for at least 30 minutes at        room temperature.    -   7. Centrifuge the plates >2000 RPM (657 rcf) for one minute.        Read plates in Microbeta after at least 5 hours incubation.        Plates can be read immediately, but signal increases over time.

Reagent addition can be done manually or with automated liquid handler.

*The final DMSO concentration in this assay is 1%.

*The positive control is in column 6; negative control is in column 18.

*Final starting concentration of compounds is 100 μM.

Part D. Data Analysis

Results were analyzed using a 2-parameter IC₅₀ fit in GraFit dataanalysis program (Erithacus Software Ltd, P. O. Bos 274, Horley, SurreyUK; www.erithacus.com).

Compounds of the several Examples above gave the following IC₅₀ data: Ex1, 475; Ex 2, 806; Ex 4, 116; Ex 5, 705; Ex 6, 695; Ex 7, 1296; Ex 8,167; Ex 9, 1309; Ex 10, 569; Ex 11, 18; Ex 12, 55; Ex 13, 55; Ex 14,735; Ex 15, 179; Ex 16, 105; Ex 17, 2591; Ex 18, 40; Ex 19, 3372; Ex 20,4647; Ex 21, 1040; Ex 22, 1362; Ex 23, 1428; Ex 24, 873; Ex 25, 685; Ex26, 673; Ex 27, 24; Ex 28, 348; Ex 29, 234; Ex 30, 154; Ex 31, 232; Ex32, 856; Ex 33, 70; Ex 35, 673; Ex 36, 924; Ex 37, 1095; Ex 38, 392; Ex41, 86; Ex 42, 56; Ex 43, 204; Ex 44, 74; Ex 45, 248; Ex 46, 128; Ex 47,88; Ex 48, 198; Ex 49, 115; Ex 50, 81; Ex 51, 161; Ex 53, 436; Ex 54,514; Ex 55, 260; Ex 56, 2111; Ex 57, 784; Ex 58, 78; Ex 59, 155; Ex 60,198; Ex 61, 112; Ex 62, 581; Ex 63, 96; Ex 64, 79; Ex 65, 55; Ex 66, 81;Ex 67, 58; Ex 68, 76; Ex 69, 25; Ex 70, 1893; Ex 71, 402; Ex 72, 171; Ex73, 533; Ex 74, 151; Ex 75, 131; Ex 76, 82; Ex 77, 52; Ex 78, 43; Ex 79,140; Ex 80, 71; Ex 81, 30; Ex 82, 108; Ex 83, 43; Ex 84, 99; Ex 85, 31;Ex 86, 142; Ex 87, 18; Ex 88, 52; Ex 89, 67; Ex 90, 173; Ex 92, 76; Ex93, 83; Ex 94, 103; Ex 95, 489; Ex 96, 57; Ex 97, 55; Ex 99, 25044; Ex100, 5747; Ex 103, 373; Ex 105, 315; Ex 106, 119; Ex 107, 75; Ex 109,207; Ex 110, 231; Ex 111, 367; Ex 112, 693; Ex 113, 248; Ex 114, 199; Ex117, 190; Ex 118, 273; Ex 119, 333; Ex 120, 270; Ex 121, 407; Ex 122,153; Ex 123, 218; Ex 124, 1052; Ex 125, 2164.

The values in this table are single-point-in-time values and repeatingthe assay run(s) my result in a somewhat different number for any giventest run and compound.

Compounds of this invention are not expected to have an unacceptableuntoward effect when used in accordance with the teachings herein aboveand when used in accordance with appropriate and usual scientific andmedical practice

The foregoing examples are provided to illustrate the invention and arenot intended to limit it in any way. What is reserved to the inventorscan be found by reference to the claims.

What is claimed is:
 1. A compound of formula (I):

wherein X and Z are selected independently from the group consisting ofhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted orsubstituted (C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl,(C₆-C₁₀)bicycloalkyl, unsubstituted or substituted heterocycloalkyl,unsubstituted or substituted heterocycloalkyl-(C₁-C₈)alkyl or-(C₂-C₈)alkenyl, unsubstituted or substituted aryl, unsubstituted orsubstituted aryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, halo, cyano, —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SR^(a), —SOR^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b); Y is H or halo; R¹ is (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted or substituted(C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted (C₆-C₁₀)bicycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, unsubstituted orsubstituted aryl, unsubstituted or substituted aryl-(C₁-C₈)alkyl or-(C₂-C₈)alkenyl, unsubstituted or substituted heteroaryl, unsubstitutedor substituted heteroaryl-(C₁-C₈)alkyl or -(C₂-C₈)alkenyl, —COR^(a),—CO₂R^(a), —CONR^(a)R^(b), or —CONR^(a)NR^(a)R^(b); R³ is hydrogen,(C₁-C₈)alkyl, cyano, trifluoromethyl, —NR^(a)R^(b), or halo; R⁶ isselected from the group consisting of hydrogen, halo, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, unsubstituted or substituted(C₃-C₈)cycloalkyl, unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl, unsubstituted or substituted(C₅-C₈)cycloalkenyl-(C₁-C₈)alkyl, (C₆-C₁₀)bicycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substitutedheterocycloalkyl-(C₁-C₈)alkyl, unsubstituted or substituted aryl,unsubstituted or substituted aryl-(C₁-C₈)alkyl, unsubstituted orsubstituted heteroaryl, unsubstituted or substitutedheteroaryl-(C₁-C₈)alkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b),—CONR^(a)NR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b),nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),—NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), —NR^(a)NR^(a)C(O)OR^(a), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b); wherein any (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by1, 2, or 3 groups independently selected from the group consisting ofhalo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a),—SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a),—OC(O)NR^(a)R^(b), heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl,and heteroaryl(C₁-C₄)alkyl; wherein any aryl or heteroaryl moiety ofsaid aryl, heteroaryl, aryl(C₁-C₄)alkyl, or heteroaryl(C₁-C₄)alkyl isoptionally substituted by 1, 2, or 3 groups independently selected fromthe group consisting of halo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,—NR^(a)R^(b), —NR^(a)C(O)R^(b), —OR^(a), —OC(O)R^(a), and—OC(O)NR^(a)R^(b); and R^(a) and R^(b) are each independently hydrogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl,(C₅-C₈)cycloalkenyl, (C₆-C₁₀)bicycloalkyl, heterocycloalkyl, aryl, orheteroaryl, wherein said (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,cycloalkyl, cycloalkenyl, bicycloalkyl, heterocycloalkyl, aryl, orheteroaryl group is optionally substituted by 1, 2, or 3 groupsindependently selected from halo, hydroxyl, (C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H,—CO₂(C₁-C₄)alkyl, —CONH₂, —CONH(C₁-C₄)alkyl,—CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl, —SO₂NH₂,—SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl); or R^(a) andR^(b) taken together with the nitrogen to which they are attachedrepresent a 5-8 membered saturated or unsaturated ring, optionallycontaining an additional heteroatom selected from oxygen, nitrogen, andsulfur, wherein said ring is optionally substituted by 1, 2, or 3 groupsindependently selected from (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, amino,(C₁-C₄)alkylamino, ((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo,(C₁-C₄)alkoxy, and (C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring isoptionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, orheteroaryl ring; or R^(a) and R^(b) taken together with the nitrogen towhich they are attached represent a 6- to 10-membered bridged bicyclicring system optionally fused to a (C₃-C₈)cycloalkyl, heterocycloalkyl,aryl, or heteroaryl ring; or a pharmaceutically acceptable salt thereof.2. The compound or pharmaceutically acceptable salt according to claim 1wherein: X and Z are selected from the group consisting of (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR^(a)R^(b), and—OR^(a); Y is H or F; R¹ is selected from the group consisting of(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;R³ is selected from the group consisting of hydrogen, (C₁-C₈)alkyl,cyano, trifluoromethyl, —NR^(a)R^(b), and halo; R⁶ is selected from thegroup consisting of hydrogen, halo, cyano, trifluoromethyl, amino,(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl, heteroaryl, acylamino,(C₂-C₈)alkynyl, aryl(C₂-C₈)alkynyl, heteroaryl(C₂-C₈)alkynyl, —SO₂R^(a),—SO₂NR^(a)R^(b), and —NR^(a)SO₂R^(b); wherein any (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, (C₂-C₈)alkynyl, aryl(C₂-C₈)alkynyl, orheteroaryl(C₂-C₈)alkynyl group is optionally substituted by 1, 2, or 3groups independently selected from halo, (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano,—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), —OC(O)NR^(a)R^(b),heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl, andheteroaryl(C₁-C₄)alkyl; and R^(a) and R^(b) are each independentlyhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₆-C₁₀)bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein said (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by1, 2, or 3 groups independently selected from halo, hydroxyl,(C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl); orR^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2, or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; or R^(a)and R^(b) taken together with the nitrogen to which they are attachedrepresent a 6- to 10-membered bridged bicyclic ring system optionallyfused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroarylring; wherein any aryl or heteroaryl group is selected independentlyfrom the group consisting of furan, thiophene, pyrrole, oxazole,thiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole,tetrazole, benzofuran, benzothiophene, benzoxazole, benzothiazole,phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, tetrazine,quinoline, cinnoline, quinazoline, quinoxaline, and naphthyridine, oranother aryl or heteroaryl group as follows:

wherein in (1), A is O, NH, or S; B is CH or N, and C is hydrogen orC₁-C₈ alkyl; or

wherein in (2), D is N or C optionally substituted by hydrogen or C₁-C₈alkyl; or

wherein in (3), E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4), J is O, S, or CO; or

wherein in (5), Q is CH or N; M is CH or N; and L/(5) is hydrogen, halo,amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), or —OR^(a); wherein any (C₁-C₈)alkyl or(C₃-C₈)cycloalkyl group is optionally substituted by 1, 2, or 3 groupsindependently selected from (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro,—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b),—NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a),—OC(O)R^(a), and —OC(O)NR^(a)R^(b); or

wherein in 6, L/(6) is NH or CH₂; or

wherein in 7, M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), or —OR^(a); wherein any (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, or heterocycloalkyl group is optionally substitutedby 1, 2, or 3 groups independently selected from (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano,—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b); or

wherein in (8), P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2;or

wherein in (9), S/(9) and T(9) are each CH, or S/(9) is CH and T(9) isN, or S/(9) is N and T/(9) is CH; R is hydrogen, amino, methyl,trifluoromethyl, or halo; U is hydrogen, halo, amino, cyano, nitro,trifluoromethyl, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)R^(b),NR^(a)C(O)R^(b), NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b), —OR^(a), or4-(1H-pyrazol-4-yl); wherein any (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl groupis optionally substituted by 1, 2, or 3 groups independently selectedfrom (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a),—SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and—OC(O)NR^(a)R^(b).
 3. The compound according to claim 1 wherein: X and Zare selected independently from the group consisting of (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR^(a)R^(b), and—OR^(a); Y is H; R¹ is (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, orheterocycloalkyl; R³ is hydrogen, (C₁-C₈)alkyl, or halo; R⁶ is hydrogen,halo, cyano, trifluoromethyl, amino, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,aryl, heteroaryl, acylamino, (C₂-C₈)alkynyl, aryl(C₂-C₈)alkynyl,heteroaryl(C₂-C₈)alkynyl, —SO₂R^(a), —SO₂NR^(a)R^(b), or—NR^(a)SO₂R^(b); wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₂-C₈)alkynyl, aryl(C₂-C₈)alkynyl, or heteroaryl(C₂-C₈)alkynyl group isoptionally substituted by 1, 2, or 3 groups independently selected fromhalo, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a),—SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a),—OC(O)NR^(a)R^(b), heterocycloalkyl, aryl, heteroaryl, aryl(C₁-C₄)alkyl,and heteroaryl(C₁-C₄)alkyl; and R^(a) and R^(b) are each independentlyhydrogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₆-C₁₀)bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl, wherein said (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C2-C8)alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl,heterocycloalkyl, aryl, or heteroaryl group is optionally substituted by1, 2, or 3 groups independently selected from halo, hydroxyl,(C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, —CO₂H, —CO₂(C₁-C₄)alkyl, —CONH₂,—CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)((C₁-C₄)alkyl), —SO₂(C₁-C₄)alkyl,—SO₂NH₂, —SO₂NH(C₁-C₄)alkyl, and —SO₂N((C₁-C₄)alkyl)((C₁-C₄)alkyl); orR^(a) and R^(b) taken together with the nitrogen to which they areattached represent a 5-8 membered saturated or unsaturated ring,optionally containing an additional heteroatom selected from oxygen,nitrogen, and sulfur, wherein said ring is optionally substituted by 1,2, or 3 groups independently selected from (C₁-C₄)alkyl,(C₁-C₄)haloalkyl, amino, (C₁-C₄)alkylamino,((C₁-C₄)alkyl)((C₁-C₄)alkyl)amino, hydroxyl, oxo, (C₁-C₄)alkoxy, and(C₁-C₄)alkoxy(C₁-C₄)alkyl, wherein said ring is optionally fused to a(C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; or R^(a)and R^(b) taken together with the nitrogen to which they are attachedrepresent a 6- to 10-membered bridged bicyclic ring system optionallyfused to a (C₃-C₈)cycloalkyl, heterocycloalkyl, aryl, or heteroarylring; wherein any aryl or heteroaryl is selected from the groupconsisting of furan, thiophene, pyrrole, oxazole, thiazole, imidazole,pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, benzofuran,benzothiophene, benzoxazole, benzothiazole, phenyl, pyridine,pyridazine, pyrimidine, pyrazine, triazine, tetrazine, quinoline,cinnoline, quinazoline, quinoxaline, and naphthyridine, or another arylor heteroaryl group as follows:

wherein in (1), A is O, NH, or S; B is CH or N, and C is hydrogen orC₁-C₈ alkyl; or

wherein in (2), D is N or C optionally substituted by hydrogen or C₁-C₈alkyl; or

wherein in (3), E is NH or CH₂; F is O or CO; and G is NH or CH₂; or

wherein in (4), J is O, S, or CO; or

wherein in (5), Q is CH or N; M is CH or N; and L/(5) is hydrogen, halo,amino, cyano, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —CONR^(a)NR^(b), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(b), —NR^(a)NR^(a)C(O)R^(b), —Nr^(a)NR^(a)C(O)NR^(a)R^(b), or—OR^(a); wherein any (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl group isoptionally substituted by 1, 2, or 3 groups independently selected from(C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl,cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a),—SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b); or

wherein in (6), L/(6) is NH or CH₂; or

wherein in (7), M/(7) is hydrogen, halo, amino, cyano, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —CONR^(a)NR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b),—NR^(a)R^(b), —NR^(a)C(O)R^(b), NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b),—NR^(a)NR^(a)C(O)NR^(a)R^(b), or —OR^(a); wherein any (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, or heterocycloalkyl group is optionally substitutedby 1, 2, or 3 groups independently selected from (C₁-C₆)alkyl,(C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₆)haloalkyl, cyano,—COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a), —SOR^(a), —SO₂R^(a),—SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b), —NR^(a)C(O)R^(b),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)C(O)OR^(a), —NR^(a)SO₂R^(b),—NR^(a)SO₂NR^(a)R^(b), —OR^(a), —OC(O)R^(a), and —OC(O)NR^(a)R^(b); or

wherein in (8), P is CH₂, NH, O, or S; Q/(8) is CH or N; and n is 0-2;or

wherein in (9), S/(9) and T(9) are each CH, or S/(9) is CH and T(9) isN, or S/(9) is N and T/(9) is CH; R is hydrogen, amino, methyl,trifluoromethyl, or halo; U is hydrogen, halo, amino, cyano, nitro,trifluoromethyl, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, —COR^(a), —CO₂R^(a),—CONR^(a)R^(b), —SO₂R^(a), —SO₂NR^(a)R^(b), —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b),—NR^(a)NR^(a)R^(b), —NR^(a)NR^(a)C(O)R^(b), —OR^(a), or4-(1H-pyrazol-4-yl); wherein any (C₁-C₈)alkyl or (C₃-C₈)cycloalkyl groupis optionally substituted by 1, 2, or 3 groups independently selectedfrom (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl,(C₁-C₆)haloalkyl, cyano, —COR^(a), —CO₂R^(a), —CONR^(a)R^(b), —SR^(a),—SOR^(a), —SO₂R^(a), —SO₂NR^(a)R^(b), nitro, —NR^(a)R^(b),—NR^(a)C(O)R^(b), —NR^(a)C(O)NR^(a)R^(b), NR^(a)C(O)OR^(a),—NR^(a)SO₂R^(b), —NR^(a)SO₂NR^(a)R^(b), —ORa, —OC(O)R^(a), and—OC(O)NR^(a)R^(b); or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1 wherein: X is methyl, ethyl, n-propyl,isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,trifluoromethyl, tetrahydropyran, hydroxymethyl, methoxymethyl, orbenzyl; Y is H; Z is methyl, ethyl, n-propyl, isopropyl,trifluoromethyl, or benzyl; R¹ is isopropyl, tert-butyl, cyclobutyl,cyclopentyl, cyclohexyl, (1-methylethyl)cyclopropyl,1,1-dioxo-tetrahydrothiophene-3-yl, 1-Me-piperidin-4-yl,tetrahydrofuran-3-yl, tetrahydropyran-4-yl, N,N-dimethyl-1-propanaminyl,benzyl, or 4-pyridyl; R³ is H, methyl, or Br; and R⁶ is methyl,cyclopropyl, propyl, dimethylamino, ethylamino, (2-hydroxyethyl)amino,2-propen-1-ylamino, 1-piperazinyl, 1-piperidinyl, 4-morpholinyl,4-piperidinylamino, tetrahydro-2H-pyran-4-ylamino, phenylamino,(phenylmethyl)amino, (4-pyridinylmethyl)amino,[2-(2-pyridinylamino)ethyl]amino, 2-(dimethylamino)ethyl]amino,4-pyridinylamino, 4-(aminocarbonyl)phenyl]amino,3-hydroxy-3-methyl-1-butyn-1-yl, 4-pyridinylethynyl, phenylethynyl,2-furanyl, 3-thienyl, 1H-pyrazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl,3-methyl-1H-indazol-5-yl, 1H-1,2,3-benzotriazol-5-yl,2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl,2-oxo-2,3-dihydro-1H-indol-6-yl, 2,1,3-benzoxadiazol-5-yl,2-amino-6-quinazolinyl, 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl,2-amino-5-pyrimidinyl, 7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl,phenyl, 2-methylphenyl, 2-nitrophenyl, 2-phenylethyl, 3-aminophenyl,4-aminophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-(methyloxy)phenyl,3-(acetylamino)phenyl, 4-(acetylamino)phenyl, 4-(aminocarbonyl)phenyl,4-(1H-pyrazol-4-yl)phenyl, 4-(aminosulfonyl)phenyl,4-(methylsulfonyl)phenyl, 4-[(dimethylamino)sulfonyl]phenyl,4-[(methylamino)carbonyl]phenyl, 4-[(methylamino)sulfonyl]phenyl,4-[(methylsulfonyl)amino]phenyl, 3-pyridinyl, 4-pyridinyl,2-(4-morpholinyl)-4-pyridinyl, 2-amino-4-pyridinyl,5-(methyloxy)-3-pyridinyl, 5-(methylsulfonyl)-3-pyridinyl,5-[(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl,5-[(phenylsulfonyl)amino]-3-pyridinyl,6-(4-methyl-1-piperazinyl)-3-pyridinyl, 6-(4-morpholinyl)-3-pyridinyl,6-(acetylamino)-3-pyridinyl, 6-(dimethylamino)-3-pyridinyl,6-(methyloxy)-3-pyridinyl, 6-[(methylamino)carbonyl]-3-pyridinyl,6-[(methylamino)sulfonyl]-3-pyridinyl, 6-methyl-3-pyridinyl, or4-pyridinyloxy; or a pharmaceutically acceptable salt thereof.
 5. Thecompound according to claim 1 which is:6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyloxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-propen-1-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-amino-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-methylethyl)-N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1-methylethyl)-N-[(4-methyl-2-oxo-6-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(6-ethyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1-methylethyl)-N-{[6-methyl-4-(1-methylethyl)-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-cyclopropyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-phenyl-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4-cyclopropyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(6-cyclopropyl-4-methyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(ethylamino)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-methylethyl)-N-{[6-methyl-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl]methyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(dimethylamino)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-morpholinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1-piperazinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(3-hydroxy-3-methyl-1-butyn-1-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-methyl-1H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(phenylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(phenylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(phenylmethyl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1,6-bis(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(4-fluorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-{4-[(dimethylamino)sulfonyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[6-(dimethylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{4-[(methylamino)sulfonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(4-aminophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[4-(acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(3-aminophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{4-[(methylamino)carbonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[3-(acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(2-amino-4-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[4-(aminosulfonyl)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{4-[(methylsulfonyl)amino]phenyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-{4-[(dimethylamino)sulfonyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-piperidinylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(4-pyridinylmethyl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-{[2-(dimethylamino)ethyl]amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-[(2-hydroxyethyl)amino]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[5-(methyloxy)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(methyloxy)-4-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(6-amino-3-pyridinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[5-(methylsulfonyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(2-furanyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{6-[(methylamino)carbonyl]-3-pyridinyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[5-[(cyclopropylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{5-[(phenylsulfonyl)amino]-3-pyridinyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-morpholinyl)-4-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(methyloxy)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[6-(acetylamino)-3-pyridinyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(2-amino-5-pyrimidinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(1H-indazol-5-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-(1H-indazol-6-yl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(1H-1,2,3-benzotriazol-5-yl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-indol-6-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylamino)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)amino]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-{[4-(aminocarbonyl)phenyl]amino}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[6-(4-morpholinyl)-3-pyridinyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(2,1,3-benzoxadiazol-5-yl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(2-amino-6-quinazolinyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-{4-[(methylamino)sulfonyl]phenyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[4-(acetylamino)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-[4-(aminocarbonyl)phenyl]-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-{[2-(2-pyridinylamino)ethyl]amino}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(7-oxo-1,5,6,7-tetrahydro-1,8-naphthyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-{6-[(methylamino)sulfonyl]-3-pyridinyl}-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(2-aminoethyl)-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-{2-[(methylsulfonyl)amino]ethyl}-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-6-methyl-1-(phenylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-amino-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-cyclobutyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-cyclopentyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-1-(1-cyclopropylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-cyclohexyl-6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-cyclopropyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;6-(4-chlorophenyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1,6-bis(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(methylsulfonyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-6-(3-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;orN-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide;or a pharmaceutically acceptable salt thereof.
 6. A PharmaceuticalComposition Comprising the Compound or Pharmaceutically acceptable saltthereof according to claim 1 and a pharmaceutically acceptableexcipient.